31 research outputs found
Estudio dee los mecanismos protectores mediados por citoquinas de la familia de interleuquina 17 durante la infecciĂłn con Trypanosoma cruzi
Tesis (Doctora en Ciencias QuĂmicas) - - Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas, 2015La tripanosomiasis americana es una zoonosis, de transmisiĂłn vectorial, transmitida por un protozoario intracelular flagelado llamado Trypanosoma cruzi. La fisiopatologĂa de la enfermedad es compleja y hasta el momento no ha sido completamente dilucida; sin embargo se sostiene que tanto el parĂĄsito como la respuesta inmune que el hospedador monta frente al mismo, podrĂan estar involucrados. Teniendo en cuenta que la respuesta inmune participa tanto en el control del parĂĄsito como en la patologĂa asociada a la infecciĂłn con T. cruzi y, que la misma puede ser blanco de eventuales estrategias de intervenciĂłn como vacunas o nuevas terapias, es clave profundizar su conocimiento. Recientemente se ha demostrado que citoquinas de la familia IL-17 contribuyen en la defensa del huĂ©sped frente a muchos patĂłgenos intracelulares. De manera similar a lo que ocurre con microorganismos extracelulares, las funciones de protecciĂłn adscriptas a IL-17 en infecciones intracelulares se circunscriben a la inducciĂłn de inflamaciĂłn y el reclutamiento de cĂ©lulas de la inmunidad innata, y sĂłlo eventualmente se vinculan con mecanismos de la inmunidad adaptativa. La hipĂłtesis que guĂa este trabajo sostiene que IL-17RA y las citoquinas que por Ă©l señalizan cumplen funciones protectoras en la infecciĂłn con T. cruzi, asociadas a la modulaciĂłn de la inmunidad innata, la inflamaciĂłn y la respuesta inmune adaptativa antiparasitaria. A lo largo de esta tesis describiĂł que las citoquinas de la familia de IL-17 que señalizan por IL-17RA juegan un papel protector clave durante la infecciĂłn intracelular con el parĂĄsito T. cruzi. Las investigaciones aquĂ realizadas respecto de los mecanismos protectores involucrados, indican que los efectos protectores de las citoquinas IL-17 dependen tanto de la modulaciĂłn de la respuesta inmune innata como de la adaptativa. En este sentido, las citoquinas IL-17 favorecen el reclutamiento de neutrĂłfilos que, en el contexto de la infecciĂłn con T. cruzi, adoptan un perfil regulatorio dependiente de la producciĂłn de IL-10 y colaboran asĂ con la regulaciĂłn de la inflamaciĂłn. Por otro lado, las mismas citoquinas actĂșan de forma directa sobre los LiT CD8+ regulando su sobrevida, activaciĂłn y agotamiento y potenciado una respuesta citotĂłxica robusta que favorece el control del parĂĄsito en tejidos. Los hallazgos de esta tesis colaboran a la comprensiĂłn de las respuestas inmunes regulatoria y citotĂłxica durante la infecciĂłn con T. cruzi y aportan conocimiento bĂĄsico sobre la capacidad regulatoria de los neutrĂłfilos y el desarrollo de respuestas citotĂłxicas. Esta informaciĂłn tiene potencial impacto en distintos contextos como otras infecciones, cĂĄncer, autoinmunidad e inmunoterapia.Fil: Tosello Boari, Jimena. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas; Argentina.Fil: Acosta RodrĂguez, Eva Virginia. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Departamento de BioquĂmica ClĂnica; Argentina.Fil: Acosta RodrĂguez, Eva Virginia. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; Argentina.Fil: Motran, Claudia Cristina. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Departamento de BioquĂmica ClĂnica; Argentina.Fil: Motran, Claudia Cristina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; Argentina.Fil: Irazoqui, Fernando. JosĂ© Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Departamento de QuĂmica BiolĂłgica; Argentina.Fil: Irazoqui, Fernando. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro de Investigaciones en QuĂmica BiolĂłgica de CĂłrdoba; Argentina.Fil: Cuadra, Gabriel Ricardo. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Departamento de FarmacologĂa; Argentina.Fil: Cuadra, Gabriel Ricardo. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Instituto de FarmacologĂa Experimental de CĂłrdoba; Argentina.Fil: Postan, Miriam. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Instituto Nacional de ParasitologĂa Dr. M. Fatala Chaben; Argentina
Tumor-induced senescent T cells promote the secretion of pro-inflammatory cytokines and angiogenic factors by human monocytes/macrophages through a mechanism that involves Tim-3 and CD40L
Solid tumors are infiltrated by immune cells where macrophages and senescent T cells are highly represented. Within the tumor microenvironment, a cross-talk between the infiltrating cells may occur conditioning the characteristic of the in situ immune response. Our previous work showed that tumors induce senescence of T cells, which are powerful suppressors of lympho-proliferation. In this study, we report that Tumor-Induced Senescent (TIS)-T cells may also modulate monocyte activation. To gain insight into this interaction, CD4+ or CD8+TIS-T or control-T cells were co-incubated with autologous monocytes under inflammatory conditions. After co-culture with CD4+ or CD8+TIS-T cells, CD14+ monocytes/macrophages (Mo/Ma) exhibit a higher expression of CD16+ cells and a reduced expression of CD206. These Mo/Ma produce nitric oxide and reactive oxygen species; however, TIS-T cells do not modify phagocyte capacity of Mo/Ma. TIS-T modulated-Mo/Ma show a higher production of pro-inflammatory cytokines (TNF, IL-1ÎČ and IL-6) and angiogenic factors (MMP-9, VEGF-A and IL-8) and a lower IL-10 and IP-10 secretion than monocytes co-cultured with controls. The mediator(s) present in the supernatant of TIS-T cell/monocyte-macrophage co-cultures promote(s) tubulogenesis and tumor-cell survival. Monocyte-modulation induced by TIS-T cells requires cell-to-cell contact. Although CD4+ shows different behavior from CD8+TIS-T cells, blocking mAbs against T-cell immunoglobulin and mucin protein 3 and CD40 ligand reduce pro-inflammatory cytokines and angiogenic factors production, indicating that these molecules are involved in monocyte/macrophage modulation by TIS-T cells. Our results revealed a novel role for TIS-T cells in human monocyte/macrophage modulation, which may have deleterious consequences for tumor progression. This modulation should be considered to best tailor the immunotherapy against cancer.Fil: Ramello, MarĂa Cecilia. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Tosello Boari, Jimena. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Canale, Fernando Pablo. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Mena, Hebe Agustina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Negrotto, Soledad. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Gastman, B. Cleveland Clinic; Estados UnidosFil: Gruppi, Adriana. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Acosta Rodriguez, Eva Virginia. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Montes, Carolina Lucia. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; Argentin
Inhibitory Receptor Expression on T Cells as a Marker of Disease Activity and Target to Regulate Effector Cellular Responses in Rheumatoid Arthritis
Objective: Inhibitory receptors are essential for the regulation of effector immune responses and may play critical roles in autoimmune diseases. We evaluated whether inhibitory receptor expression on T cells from patients with rheumatoid arthritis (RA) were correlated with immune activation, disease activity, and response to treatment, as well as whether inhibitory receptorâmediated pathways were functional. Methods: Using flow cytometry, we performed extensive phenotypic and functional evaluation of CD4+ and CD8+ T cells from the blood and synovial fluid (SF) of RA patients ex vivo and after culture. The relationship of each parameter with the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) and response to treatment was examined. Results: In RA patients with low levels of T cell activation, inhibitory receptor expression showed an inverse relationship with the DAS28-ESR. The frequency of T cells expressing multiple inhibitory receptors was reduced in untreated RA patients but returned to normal levels in treated patients. RA patients who responded to treatment showed an augmented frequency of inhibitory receptorâexpressing T cells that correlated with reduced inflammatory cytokine production in comparison to nonresponders. Higher frequencies of effector and memory T cells that expressed multiple inhibitory receptors were seen in SF than in peripheral blood. Notably, inhibitory pathways were operative in blood and synovial T cells from all RA patients, although cells from nonresponder patients were less sensitive to inhibition. Conclusion: Inhibitory receptor expression on T cells from RA patients is inversely correlated with effector T cell function and disease activity and may predict response to treatment. Furthermore, different inhibitory pathways are functional and cooperatively suppress synovial T cells, providing a rationale for new treatment strategies to regulate acute local inflammation.Fil: Onofrio, Luisina InĂ©s. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; Argentina. Universidad Nacional de CĂłrdoba. Facultad de Medicina. Hospital Nacional de ClĂnicas; ArgentinaFil: Zacca, EstefanĂa. Universidad Nacional de CĂłrdoba. Facultad de Medicina. Hospital Nacional de ClĂnicas; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Ferrero, Paola Virginia. Universidad Nacional de CĂłrdoba. Facultad de Medicina. Hospital Nacional de ClĂnicas; ArgentinaFil: Acosta, Cristina. Universidad Nacional de CĂłrdoba. Facultad de Medicina. Hospital Nacional de ClĂnicas; ArgentinaFil: Mussano, Eduardo. Universidad Nacional de CĂłrdoba. Facultad de Medicina. Hospital Nacional de ClĂnicas; ArgentinaFil: Onetti, Laura. Universidad Nacional de CĂłrdoba. Facultad de Medicina. Hospital Nacional de ClĂnicas; ArgentinaFil: Cadile, Isaac. Universidad Nacional de CĂłrdoba. Facultad de Medicina. Hospital Nacional de ClĂnicas; ArgentinaFil: Gazzoni, M. Victoria. Universidad Nacional de CĂłrdoba. Facultad de Medicina. Hospital Nacional de ClĂnicas; ArgentinaFil: Jurado, RaĂșl. Universidad Nacional de CĂłrdoba. Facultad de Medicina. Hospital Nacional de ClĂnicas; ArgentinaFil: Tosello Boari, Jimena. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Ramello, MarĂa Cecilia. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Montes, Carolina Lucia. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Gruppi, Adriana. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Acosta Rodriguez, Eva Virginia. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; Argentin
IL-17RA-signaling modulates CD8+ T Cell survival and exhaustion during trypanosoma cruzi infection
The IL-17 family contributes to host defense against many intracellular pathogens by mechanisms that are not fully understood. CD8+ T lymphocytes are key elements against intracellular microbes, and their survival and ability to mount cytotoxic responses are orchestrated by several cytokines. Here, we demonstrated that IL-17RA-signaling cytokines sustain pathogen-specific CD8+ T cell immunity. The absence of IL-17RA and IL-17A/F during Trypanosoma cruzi infection resulted in increased tissue parasitism and reduced frequency of parasite-specific CD8+ T cells. Impaired IL-17RA-signaling in vivo increased apoptosis of parasite-specific CD8+ T cells, while in vitro recombinant IL-17 down-regulated the pro-Apoptotic protein BAD and promoted the survival of activated CD8+ T cells. Phenotypic, functional, and transcriptomic profiling showed that T. cruzi-specific CD8+ T cells derived from IL-17RA-deficient mice presented features of cell dysfunction. PD-L1 blockade partially restored the magnitude of CD8+ T cell responses and parasite control in these mice. Adoptive transfer experiments established that IL-17RA-signaling is intrinsically required for the proper maintenance of functional effector CD8+ T cells. Altogether, our results identify IL-17RA and IL-17A as critical factors for sustaining CD8+ T cell immunity to T. cruzi.Fil: Tosello Boari, Jimena. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; Argentina. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Departamento de BioquĂmica ClĂnica; ArgentinaFil: Araujo Furlan, Cintia Liliana. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Departamento de BioquĂmica ClĂnica; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Fiocca Vernengo, Facundo. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Departamento de BioquĂmica ClĂnica; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Rodriguez, Constanza. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; Argentina. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Departamento de BioquĂmica ClĂnica; ArgentinaFil: Ramello, MarĂa Cecilia. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Departamento de BioquĂmica ClĂnica; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Amezcua Vesely, Maria Carolina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; Argentina. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Departamento de BioquĂmica ClĂnica; ArgentinaFil: Gorosito Serran, Melisa. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; Argentina. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Departamento de BioquĂmica ClĂnica; ArgentinaFil: Nuñez, NicolĂĄs G.. Institute Curie; Francia. Institut National de la SantĂ© et de la Recherche MĂ©dicale; FranciaFil: Richer, Wilfrid. Institut National de la SantĂ© et de la Recherche MĂ©dicale; Francia. Institute Curie; FranciaFil: Piaggio, Eliane. Institut National de la SantĂ© et de la Recherche MĂ©dicale; Francia. Institute Curie; FranciaFil: Montes, Carolina Lucia. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; Argentina. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Departamento de BioquĂmica ClĂnica; ArgentinaFil: Gruppi, Adriana. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Departamento de BioquĂmica ClĂnica; Argentina. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Acosta Rodriguez, Eva Virginia. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; Argentina. Universidad Nacional de CĂłrdoba. Facultad de Ciencias QuĂmicas. Departamento de BioquĂmica ClĂnica; Argentin
Limited Foxp3+ Regulatory T Cells Response During Acute Trypanosoma cruzi Infection Is Required to Allow the Emergence of Robust Parasite-Specific CD8+ T Cell Immunity
While it is now acknowledged that CD4+ T cells expressing CD25 and Foxp3 (Treg cells) regulate immune responses and, consequently, influence the pathogenesis of infectious diseases, the regulatory response mediated by Treg cells upon infection by Trypanosoma cruzi was still poorly characterized. In order to understand the role of Treg cells during infection by this protozoan parasite, we determined in time and space the magnitude of the regulatory response and the phenotypic, functional and transcriptional features of the Treg cell population in infected mice. Contrary to the accumulation of Treg cells reported in most chronic infections in mice and humans, experimental T. cruzi infection was characterized by sustained numbers but decreased relative frequency of Treg cells. The reduction in Treg cell frequency resulted from a massive accumulation of effector immune cells, and inversely correlated with the magnitude of the effector immune response as well as with emergence of acute immunopathology. In order to understand the causes underlying the marked reduction in Treg cell frequency, we evaluated the dynamics of the Treg cell population and found a low proliferation rate and limited accrual of peripheral Treg cells during infection. We also observed that Treg cells became activated and acquired a phenotypic and transcriptional profile consistent with suppression of type 1 inflammatory responses. To assess the biological relevance of the relative reduction in Treg cells frequency observed during T. cruzi infection, we transferred in vitro differentiated Treg cells at early moments, when the deregulation of the ratio between regulatory and conventional T cells becomes significant. Intravenous injection of Treg cells dampened parasite-specific CD8+ T cell immunity and affected parasite control in blood and tissues. Altogether, our results show that limited Treg cell response during the acute phase of T. cruzi infection enables the emergence of protective anti-parasite CD8+ T cell immunity and critically influences host resistance
Unconventional pro-inflammatory CD4+ T cell response in B cell-deficient mice infected with Trypanosoma cruzi
Chagas disease, caused by the parasite Trypanosoma cruzi, is endemic in Latin America but has become a global public health concern by migration of infected people. It has been reported that parasite persistence as well as the intensity of the inflammatory immune response are determinants of the clinical manifestations of the disease. Even though inflammation is indispensable for host defense, when deregulated, it can contribute to tissue injury and organ dysfunction. Here, we report the importance of B cells in conditioning T cell response in T. cruzi infection. Mice deficient in mature B cells (muMT mice) infected with T. cruzi exhibited an increase in plasma TNF concentration, TNF-producing CD4+ T cells, and mortality. The increase in TNF-producing CD4+ T cells was accompanied by a reduction in IFNÎł+CD4+ T cells and a decrease of the frequency of regulatory Foxp3+, IL-10+, and IL17+CD4+ T cells populations. The CD4+ T cell population activated by T. cruzi infection, in absence of mature B cells, had a high frequency of Ly6C+ cells and showed a lower expression of inhibitory molecules such as CTLA-4, PD-1, and LAG3. CD4+ T cells from infected muMT mice presented a high frequency of CD62LhiCD44â cells, which is commonly associated with a naĂŻve phenotype. Through transfer experiments we demonstrated that CD4+ T cells from infected muMT mice were able to condition the CD4+ T cells response from infected wild-type mice. Interestingly, using Blimp-flox/flox-CD23icre mice we observed that in absence of plasmablast/plasma cell T. cruzi-infected mice exhibited a higher number of TNF-producing CD4+ T cells. Our results showed that the absence of B cells during T. cruzi infection affected the T cell response at different levels and generated a favorable scenario for unconventional activation of CD4+ T cell leading to an uncontrolled effector response and inflammation. The product of B cell differentiation, the plasmablast/plasma cells, could be able to regulate TNF-producing CD4+ T cells since their absence favor the increase of the number of TNF+ CD4+ in T. cruzi-infected miceResearch reported in this publication was supported by the
Agencia Nacional de PromociĂłn CientĂfica y TĂ©cnica (Foncyt,
PICT 2011-2647 and PICT 2015-0645), Consejo Nacional de
Investigaciones CientĂficas y TĂ©cnicas, CONICET, (PIP 112-
20110100378), the SecretarĂa de Ciencia y TĂ©cnica-Universidad
Nacional de CĂłrdoba, and the National Institute of Allergy and
Infectious Diseases of the National Institutes of Health under
Award Number R01AI116432-01
Extrafollicular plasmablast present in the acute phase of infections express high levels of PD-L1 and are able to limit T cell respose
During infections with protozoan parasites or some viruses, T cell immunosuppression is generated simultaneously with a high B cell activation. It has been described that, as well as producing antibodies, plasmablasts, the differentiation product of activated B cells, can condition the development of protective immunity in infections. Here, we show that, in T. cruzi infection, all the plasmablasts detected during the acute phase of the infection had higher surface expression of PD-L1 than other mononuclear cells. PD-L1hi plasmablasts were induced in vivo in a BCR-specific manner and required help from Bcl-6+CD4+T cells. PD-L1hi expression was not a characteristic of all antibody-secreting cells since plasma cells found during the chronic phase of infection expressed PD-L1 but at lower levels. PD-L1hi plasmablasts were also present in mice infected with Plasmodium or with lymphocytic choriomeningitis virus, but not in mice with autoimmune disorders or immunized with T cell-dependent antigens. In vitro experiments showed that PD-L1hi plasmablasts suppressed the T cell response, partially via PD-L1. Thus, this study reveals that extrafollicular PD-L1hi plasmablasts, whose peaks of response precede the peak of germinal center response, may have a modulatory function in infections, thus influencing T cell response.Fil: Gorosito Serran, Melisa. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Fiocca Vernengo, Facundo. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Almada, Laura. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Beccaria, Cristian Gabriel. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Gazzoni, Yamila Natali. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Canete, Pablo F.. Australian National University; ArubaFil: Roco, Jonathan A.. Australian National University; ArubaFil: Tosello Boari, Jimena. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Ramello, MarĂa Cecilia. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Wehrens, Ellen. University of California; Estados UnidosFil: Cai, Yeping. Australian National University; ArubaFil: Zuniga, Elina Isabel. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas; ArgentinaFil: Montes, Carolina Lucia. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Cockburn, Ian A.. Australian National University; ArubaFil: Acosta Rodriguez, Eva Virginia. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Vinuesa, Carola G.. Australian National University; ArubaFil: Gruppi, Adriana. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; Argentin
IL-17RA-Signaling Modulates CD8+ T Cell Survival and Exhaustion During Trypanosoma cruzi Infection
The IL-17 family contributes to host defense against many intracellular pathogens by mechanisms that are not fully understood. CD8+ T lymphocytes are key elements against intracellular microbes, and their survival and ability to mount cytotoxic responses are orchestrated by several cytokines. Here, we demonstrated that IL-17RA-signaling cytokines sustain pathogen-specific CD8+ T cell immunity. The absence of IL-17RA and IL-17A/F during Trypanosoma cruzi infection resulted in increased tissue parasitism and reduced frequency of parasite-specific CD8+ T cells. Impaired IL-17RA-signaling in vivo increased apoptosis of parasite-specific CD8+ T cells, while in vitro recombinant IL-17 down-regulated the pro-apoptotic protein BAD and promoted the survival of activated CD8+ T cells. Phenotypic, functional, and transcriptomic profiling showed that T. cruzi-specific CD8+ T cells derived from IL-17RA-deficient mice presented features of cell dysfunction. PD-L1 blockade partially restored the magnitude of CD8+ T cell responses and parasite control in these mice. Adoptive transfer experiments established that IL-17RA-signaling is intrinsically required for the proper maintenance of functional effector CD8+ T cells. Altogether, our results identify IL-17RA and IL-17A as critical factors for sustaining CD8+ T cell immunity to T. cruzi
IL-17RA Signaling Reduces Inflammation and Mortality during Trypanosoma cruzi Infection by Recruiting Suppressive IL-10-Producing Neutrophils
Members of the IL-17 cytokine family play an important role in protection against pathogens through the induction of different effector mechanisms. We determined that IL-17A, IL-17E and IL-17F are produced during the acute phase of T. cruzi infection. Using IL-17RA knockout (KO) mice, we demonstrate that IL-17RA, the common receptor subunit for many IL-17 family members, is required for host resistance during T. cruzi infection. Furthermore, infected IL-17RA KO mice that lack of response to several IL-17 cytokines showed amplified inflammatory responses with exuberant IFN-Îł and TNF production that promoted hepatic damage and mortality. Absence of IL-17RA during T. cruzi infection resulted in reduced CXCL1 and CXCL2 expression in spleen and liver and limited neutrophil recruitment. T. cruzi-stimulated neutrophils secreted IL-10 and showed an IL-10-dependent suppressive phenotype in vitro inhibiting T-cell proliferation and IFN-Îł production. Specific depletion of Ly-6G+ neutrophils in vivo during T. cruzi infection raised parasitemia and serum IFN-Îł concentration and resulted in increased liver pathology in WT mice and overwhelming wasting disease in IL-17RA KO mice. Adoptively transferred neutrophils were unable to migrate to tissues and to restore resistant phenotype in infected IL-17RA KO mice but migrated to spleen and liver of infected WT mice and downregulated IFN-Îł production and increased survival in an IL-10 dependent manner. Our results underscore the role of IL-17RA in the modulation of IFN-Îł-mediated inflammatory responses during infections and uncover a previously unrecognized regulatory mechanism that involves the IL-17RA-mediated recruitment of suppressive IL-10-producing neutrophils
Adoptive transfer of isolated bone marrow neutrophil
Adoptive transfer experiments of specific cell populations are widely used methods to assess the role of the injected population on an ongoing process. In the last years, new and unprecedented roles in the regulation of immune responses have been reported for neutrophils. The following protocol is to be used to isolate neutrophils from bone marrow and to inject them in an appropriate host to test the role of neutrophils during infection, inflammation or other pathological conditions.Fil: Tosello Boari, Jimena. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; ArgentinaFil: Acosta Rodriguez, Eva Virginia. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico CĂłrdoba. Centro de Investigaciones en BioquĂmica ClĂnica e InmunologĂa; Argentin