Are human V\u3b42pos T cells really resistant to aging and Human Cytomegalovirus infection?

In their recent paper, Weili Xu et al. [1] described the different behaviors of V\u3b41pos and V\u3b42pos T cell subsets in response to lifelong stress and claimed that V\u3b42pos T cells are not affected by aging and Human Cytomegalovirus (HCMV) infection. While we agree that these two \u3b3\u3b4 T cell subsets diverge both in phenotype/function and in tissue distribution, we are somewhat surprised that authors did not take into account the several previously published and contradictory experimental evidence in regards to senescence of V\u3b42pos T cells [2,3]. These latter studies reported that HCMV infection not only induces a clonal expansion of a distinct V\u3b39neg/V\u3b42pos T cell subset, but also determines a concomitant adaptive differentiation from CD27high na\uefve cells to CD27low/neg terminal-effectors. However, Weili Xu et al. argued that the expression and kinetics of both CD27 and CD45RA surface markers do not change and follow the homeostatic changes of V\u3b42pos T cells. This statement goes in the opposite direction to previously reported findings as the CD27/CD45RA phenotype has been shown to mark the maturation and differentiation (TNa\uefve, TCentral-Memory, Teffector-Memory and TEffectory-Memory RA) of V\u3b42pos T cells. Indeed, the different surface expression of both CD27 and CD45 parallel the progressive decrease of telomere length, the proliferative capacity as well as the different effector-functions and resistance to death of V\u3b42+ T cells in response to antigens and homeostatic cytokines [4,5]. Hence, we believe that these controversial issues require further discussion beyond the unilateral conclusion given by the study of Weili Xu et al

Clonal expansion shapes the human V\u3b41T cell receptor repertoire.

Cellular and Molecular Immunology aims to report the dynamic progress being made in China and abroad in immunological research, and welcomes high-quality Research Articles, Reviews and Brief Reports across a broad range of topics including, but not limited to, clinical immunology, comparative immunology, immunobiology, immunogenetics, immunological techniques, immunopathology, immunopharmacology, infection immunology, neuroimmunology, transplantation immunology, tumor immunology, and veterinary immunology

Progression-free survival as a surrogate endpoint of overall survival in patients with metastatic colorectal cancer

Background: In many clinical trials designed to assess the efficacy of anticancer treatments, overall survival (OS) is often used as a primary endpoint despite its several points of weakness. Methods: This study evaluated the role of progression-free survival (PFS) in the first three lines of treatment as a potential surrogate endpoint of OS in patients with metastatic colorectal cancer (MCRC). One hundred and twenty patients with MCRC were enrolled in this study. The median PFS of the first-, second-, and third-lines of treatment and the OS were evaluated. The correlation between the time to progression and the OS was analyzed. The median PFS of the three lines of treatment were 8.5, 5, and 3 months, respectively. Results: The median OS was 32.4 months. A modest correlation was found between the PFS to the first-line treatment with Folfox\u2013avastin and OS. Similar data were obtained with the second-line treatment. However, no correlation was found between the PFS and OS during the third-line treatment. The regression analysis revealed that PFS is predictive of OS. Conclusion: In brief, the PFS of the first- and second-lines of treatment could be a good candidate as a surrogate endpoint of OS in patients with MCRC

Chemotherapy accelerates immune-senescence and functional impairments of Vδ2pos T cells in elderly patients affected by liver metastatic colorectal cancer.

Human (gamma delta) γδ T cells are unconventional innate-like lymphocytes displaying a broad array of anti-tumor activities with promising perspectives in cancer immunotherapy. In this context, Vδ2pos T cells represent the preferential target of several immunotherapy protocols against solid tumors. However, the impact of both aging and chemotherapy (CHT) on Vδ2pos T cells is still unknown. The present study evaluates with multi-parametric flow cytometry the frequencies, terminal differentiation, senescence and effector-functions of peripheral blood and tumor infiltrating Vδ2pos T cells purified from liver metastases (CLM) of patients affected by colorectal cancer (CRC) compared to those of sex- and age-matched healthy donors. The peripheral blood of CLM patients underwent CHT is characterized by decreased amounts of Vδ2pos T cells showing a relative increase of terminally-differentiated CD27neg/CD45RApos (TEMRA) cells. The enrichment of this latter subset is associated with an increased expression of the senescent marker CD57. The acquisition of CD57 on TEMRA Vδ2pos T cells is also coupled with impairments in cytotoxicity and production of TNF-α and IFN-γ. These features resemble the acquisition of an immune-senescent profile by Vδ2pos T cells from CLM patients that received CHT, a phenomenon that is also associated with the loss of the co-stimulatory marker CD28 and with the induced expression of CD16. The group of CLM patients underwent CHT and older than 60 years old showed higher frequencies of CD57pos and TEMRA Vδ2pos T cells. Similar results were found for tumor infiltrating Vδ2pos T cell subset purified from CLM specimens of patients treated with CHT. The toxicity of CHT regimens also affects the homeostasis of Vδ2pos T cells by inducing higher frequencies of circulating CD57pos TEMRA subset in CLM underwent CHT and younger than 60 years old. Taken together, our data demonstrate that the enrichment of senescent Vδ2pos T cells in CLM patients is not only induced by patients' aging but also by the toxicity of CHT that further accelerates the accumulation of CD57pos TEMRA cells highly dysfunctional in their anti-tumor activities. These results are important to both predict the clinical outcome of CLM and to optimize those protocols of cell cancer immunotherapy employing unconventional Vδ2pos T cells

Skewed Differentiation of Circulating Vγ9Vδ2 T Lymphocytes in Melanoma and Impact on Clinical Outcome

Objective The aim of this study was to evaluate over time circulating γδ T lymphocytes in melanoma patients in terms of frequency, effector functions, and relationship with clinical stage and evolution, by comparing preoperative values to those obtained at a mean follow-up of 36 months or in the event of recurrence or disease progression, and to those of healthy controls. Also, we correlated the presence of tumor-infiltrating γδ T lymphocytes with clinical evolution of melanoma. Results Mean frequencies of circulating γδ T cells before and after melanoma removal were very similar and comparable to healthy subjects, but patients who progressed to stage III or IV showed a significantly decreased frequency of circulating Vγ9Vδ2 T cells. The distribution of Vγ9Vδ2 memory and effector subsets was similar in healthy subjects and melanoma patients at diagnosis, but circulating γδ T cells of patients after melanoma removal had a skewed terminally-differentiated effector memory phenotype. Highly suggestive of progressive differentiation toward a cytotoxic phenotype, Vγ9Vδ2T cells from patients at follow up had increased cytotoxic potential and limited cytokine production capability, while the opposite pattern was detected in Vγ9Vδ2T cells from patients before melanoma removal. Conclusions Follow-up data also showed that tumor infiltrating γδ T cells were significantly associated with lower mortality and relapse rates, suggesting that they may serve as a prognostic biomarker, for human melanom

Mycobacterium tuberculosis Drives Expansion of Low-Density Neutrophils Equipped With Regulatory Activities

In human tuberculosis (TB) neutrophils represent the most commonly infected phagocyte but their role in protection and pathology is highly contradictory. Moreover, a subset of low-density neutrophils (LDNs) has been identified in TB, but their functions remain unclear. Here, we have analyzed total neutrophils and their low-density and normal-density (NDNs) subsets in patients with active TB disease, in terms of frequency, phenotype, functional features, and gene expression signature. Full-blood counts from Healthy Donors (H.D.), Latent TB infected, active TB, and cured TB patients were performed. Frequency, phenotype, burst activity, and suppressor T cell activity of the two different subsets were assessed by flow cytometry while NETosis and phagocytosis were evaluated by confocal microscopy. Expression analysis was performed by using the semi-quantitative RT-PCR array technology. Elevated numbers of total neutrophils and a high neutrophil/lymphocyte ratio distinguished patients with active TB from all the other groups. PBMCs of patients with active TB disease contained elevated percentages of LDNs compared with those of H.D., with an increased expression of CD66b, CD33, CD15, and CD16 compared to NDNs. Transcriptomic analysis of LDNs and NDNs purified from the peripheral blood of TB patients identified 12 genes differentially expressed: CCL5, CCR5, CD4, IL10, LYZ, and STAT4 were upregulated, while CXCL8, IFNAR1, NFKB1A, STAT1, TICAM1, and TNF were downregulated in LDNs, as compared to NDNs. Differently than NDNs, LDNs failed to phagocyte live Mycobacterium tuberculosis (M. tuberculosis) bacilli, to make oxidative burst and NETosis, but caused significant suppression of antigen-specific and polyclonal T cell proliferation which was partially mediated by IL-10. These insights add a little dowel of knowledge in understanding the pathogenesis of human TB

Does sars-cov-2 trigger stress-induced autoimmunity by molecular mimicry? A hypothesis

Viruses can generate molecular mimicry phenomena within their hosts. Why should severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) not be considered one of these? Information in this short review suggests that it might be so and, thus, encourages research aiming at testing this possibility. We propose, as a working hypothesis, that the virus induces antibodies and that some of them crossreact with host’s antigens, thus eliciting autoimmune phenomena with devasting consequences in various tissues and organs. If confirmed, by in vitro and in vivo tests, this could drive researchers to find effective treatments against the virus

IL-17 polarization of MAIT cells is derived from the activation of two different pathways

MAIT cells are expanded in salivary glands of patients with Sjogren's syndrome and are IL-17 polarized. IL-7 and IL-23 induce IL-17 production activating two different pathways: IL-7 stimulation induces in fact a significant STAT3 and HIF1alpha upregulation, conversely, IL-23 stimulation significantly induces RORc overexpression in MAIT cells of patients with Sjogren's syndrome

Invariant NKT cells are expanded in peripheral blood but are undetectable in salivary glands of patients with primary Sj\uf6gren's syndrome.

OBJECTIVES: Invariant NKT (iNKT) cells play a role in regulating the function of autoreactive B cells before their entry into germinal centres. Absence and/or reduction of iNKT cells have been demonstrated in patients with systemic lupus erythematosus (SLE) together with an increase of autoreactive B cell activity. Primary Sj\uf6gren's syndrome (pSS) is a systemic autoimmune disease in which lymphocyte infiltration and organisation in lymphoid structures of inflamed salivary glands occurs. The aim of the study was to investigate the percentage and function of iNKT in the salivary glands and peripheral blood of patients with pSS. METHODS: Minor salivary gland biopsies were obtained from patients with pSS and with non-specific chronic sialoadenitis (nSS). Flow cytometry analysis of CD1d/\u3b1-GalactosylCeramide (\u3b1-GalCer) tetramer positive cells, producing IFN-\u3b3 and IL-17, and quantitative gene expression analysis by TaqMan real-time PCR for V\u3b124 were performed on salivary glands biopsies and peripheral blood samples obtained from patients and controls. Flow cytometry and immunofluorescence analysis for autoreactive B lymphocytes and ELISA for anti-SSA antibodies (Ab) detection were also performed. RESULTS: An increase of iNKT was detected ex vivo in peripheral blood of pSS patients; after \u3b1-GalCer stimulation this subset produce IL-17 and IFN-iNKT were undetectable in the salivary glands of pSS patients and anti-SSA specific B cells were found in target tissue. Invariant NKT cells were able to inhibit autoantibody production by B cells obtained from salivary glands of pSS. CONCLUSIONS: Impaired iNKT migration to inflamed sites might induce the activation of autoreactive B cells specific for SSA-antigen in salivary glands of pSS patients