pMHC affinity controls duration of CD8+ T cell&-DCinteractions and imprints timing of effector differentiationversus expansion

During adaptive immune responses, CD8+ T cells with low TCR affinities are released early into the circulation before high-affinityclones become dominant at later time points. How functional avidity maturation is orchestrated in lymphoid tissue andhow low-affinity cells contribute to host protection remains unclear. In this study, we used intravital imaging of reactive lymphnodes (LNs) to show that T cells rapidly attached to dendritic cells irrespective of TCR affinity, whereas one day later, theduration of these stable interactions ceased progressively with lowering peptide major histocompatibility complex (pMHC)affinity. This correlated inversely BATF (basic leucine zipper transcription factor, ATF-like) and IRF4 (interferon-regulatedfactor 4) induction and timing of effector differentiation, as low affinity&-primed T cells acquired cytotoxic activity earlierthan high affinity&-primed ones. After activation, low-affinity effector CD8+ T cells accumulated at efferent lymphatic vesselsfor egress, whereas high affinity&-stimulated CD8+ T cells moved to interfollicular regions in a CXCR3-dependent manner forsustained pMHC stimulation and prolonged expansion. The early release of low-affinity effector T cells led to rapid target cellelimination outside reactive LNs. Our data provide a model for affinity-dependent spatiotemporal orchestration of CD8+ T cellactivation inside LNs leading to functional avidity maturation and uncover a role for low-affinity effector T cells during earlymicrobial containment.This work was supported by a Novartis Research grant (to A.J. Ozga) and Swiss National Science Foundation grants (31003A_135649 and CR23I3_156234 to J.V. Stein and CRS II3_141918 to J.V. Stein and J. Sharpe). J. Ripoll acknowledges support from European Commission FP7 Career Integration Grants (HIGH-THROUGHPUT TOMO), European Commission FP7 Marie Curie Actions (grant 2PM), and the Ministerio de Economía y Competitividad (grant FIS2013-41802-R). J. Sharpe acknowledges support from the Ministerio de Economía y Competitividad, Centro de Excelencia Severo Ochoa 2013–2017 (grant SEV-2012-0208)

Unravelling the convoluted biological roles of type I interferons (IFN-Is) in infection and immunity: a way forward for therapeutics and vaccine design

It has been well-established that type I interferons (IFN-Is) have pleiotropic effects and play an early central role in the control of many acute viral infections. However, their pleiotropic effects are not always beneficial to the host and in fact several reports suggest that the induction of IFN-Is exacerbate disease outcomes against some bacterial and chronic viral infections. In this brief review, we probe into this mystery and try to develop answers based on past and recent studies evaluating the roles of IFN-Is in infection and immunity as this is vital for developing effective IFN-Is based therapeutics and vaccines. We also discuss the biological roles of an emerging IFN-I, namely IFN-ε, and discuss its potential use as a mucosal therapeutic and/or vaccine adjuvant. Overall, we anticipate the discussions generated in this review will provide new insights for better exploiting the biological functions of IFN-Is in developing efficacious therapeutics and vaccines in the future.Danushka Kumara Wijesundara, Yank Xi and Charani Ranasingh

Type I Interferons Induce T Regulatory 1 Responses and Restrict Humoral Immunity during Experimental Malaria

We thank Christopher Hunter and Bob Axtell for critical feedback, and the Flow Cytometry Laboratory at OUHSC for technical assistance.Author Summary Humoral immunity is essential for host resistance to pathogens that trigger highly inflammatory immune responses, including Plasmodium parasites, the causative agents of malaria. Long-lived, secreted antibody responses depend on a specialized subset of CD4 T cells called T follicular helper (Tfh) cells. However, anti-Plasmodium humoral immunity is often short-lived, non-sterilizing, and immunity rapidly wanes, leaving individuals susceptible to repeated bouts of malaria. Here we explored the relationship between inflammatory type I interferons, the regulation of pathogen-specific CD4 T cell responses, and humoral immunity using models of experimental malaria and systemic virus infection. We identified that type I interferons promote the formation and accumulation of pathogen-specific CD4 T regulatory 1 cells that co-express interferon-gamma and interleukin-10. Moreover, we show that the combined activity of interferon-gamma and interleukin-10 limits the magnitude of infection-induced Tfh responses, the secretion of parasite-specific secreted antibody, and parasite control. Our study provides new insight into the regulation of T regulatory 1 responses and humoral immunity during inflammatory immune reactions against systemic infections.Yeshttp://www.plospathogens.org/static/editorial#pee

The Timing of Stimulation and IL-2 Signaling Regulate Secondary CD8 T Cell Responses

<div><p>Abstract</p><p>Memory CD8 T cells provide protection to immune hosts by eliminating pathogen-infected cells during re-infection. While parameters influencing the generation of primary (1°) CD8 T cells are well established, the factors controlling the development of secondary (2°) CD8 T cell responses remain largely unknown. Here, we address the mechanisms involved in the generation and development of 2° memory (M) CD8 T cells. We observed that the time at which 1° M CD8 T cells enter into immune response impacts their fate and differentiation into 2° M CD8 T cells. Late-entry of 1° M CD8 T cells into an immune response (relative to the onset of infection) not only facilitated the expression of transcription factors associated with memory formation in 2° effector CD8 T cells, but also influenced the ability of 2° M CD8 T cells to localize within the lymph nodes, produce IL-2, and undergo Ag-driven proliferation. The timing of stimulation of 1° M CD8 T cells also impacted the duration of expression of the high-affinity IL-2 receptor (CD25) on 2° effector CD8 T cells and their sensitivity to IL-2 signaling. Importantly, by blocking or enhancing IL-2 signaling in developing 2° CD8 T cells, we provide direct evidence for the role of IL-2 in controlling the differentiation of Ag-driven 2° CD8 T cell responses. Thus, our data suggest that the process of 1° M to 2° M CD8 T cell differentiation is not fixed and can be manipulated, a notion with relevance for the design of future prime-boost vaccination approaches.</p></div

The timing of stimulation modulates the function of 2° M CD8 T cells.

<p><b>A)</b> Total numbers of 2° M Thy1.1 P14 CD8 T cells in mL of PBL, and in the spleen, lung, and LN of individual mice from ‘early’ and ‘late’ group of mice 7 months after the initiation of the experiment. <b>B)</b> Representative dot plots showing cytokine production by 2° M P14 CD8 T cells, isolated from the spleen of individual mice after short <i>ex vivo</i> incubation in the presence of GP33 peptide. Numbers represent the percentage of 2° M P14 CD8 T cells that were positive for IFNγ and IL-2. <b>C)</b> Percentage of IFNγ producing 2° M P14 CD8 T cells that co-produce IL-2. Dots represent individual mice and the line represents the mean. <b>D)</b> Experimental design, 2° M Thy1.1 P14 CD8 T cells from ‘early’ and ‘late’ groups of mice were isolated on day 260 after transfer by positive selection and transferred in equal numbers (1.5x10⁴ cells/mouse, i.v.) into naïve B6 Thy1.2/1.2 recipients 1 day before Att LM-GP33 (1x10⁷ CFU/mouse i.v.) infection. <b>E)</b> Representative histograms showing the expression of the molecules CD27, CD62L, and KLRG1 on transferred 2° M P14 CD8 T cells from ‘early’ and late’ groups of mice. Shaded graphs represent isotype control staining and open graphs represent specific Ab staining on gated 2° M Thy1.1 P14 CD8 T cells. <b>F)</b> Representative dot plots showing 3° expansion of P14 CD8 T cells on day 6 after infection with Att LM-GP33. Numbers indicate the percentage of P14 CD8 T cells in the PBL. <b>G)</b> Percentage of P14 CD8 T cells in the PBL of individual mice on day 6 is shown. Dots represent individual mice and the line represents the mean. Data are of 5 mice per group and representative of 2–3 independent experiments. The p values are indicated; ns- not significant.</p