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Targeted deletion of BAFF causes severe deficiency of splenic B cells. BAFF-R is commonly thought to signal to nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase dependent noncanonical NF-κB RelB. However, RelB-deficient mice have normal B-cell numbers. Recent studies showed that BAFF also signals to the canonical NF-κB pathway, and we found that both RelB and cRel are persistently activated, suggesting BAFF signaling coordinates both pathways to ensure robust B-cell development. Indeed, we report now that combined loss of these 2 NF-κB family members leads to impaired BAFF-mediated survival and development in vitro. Although single deletion of RelB and cRel was dispensable for normal B-cell development, double knockout mice displayed an early B-cell developmental blockade and decreased mature B cells. Despite disorganized splenic architecture in Relb(-/-)cRel(-/-) mice, generation of mixed-mouse chimeras established the developmental phenotype to be B-cell intrinsic. Together, our results indicate that BAFF signals coordinate both RelB and cRel activities to ensure survival during peripheral B-cell maturation.

Tissue-resident memory CD8+ T cells (TRM) are optimally positioned at common sites of pathogen exposure, where they elicit rapid and robust antiviral immune responses. However, the molecular signals controlling tissue residency and homeostasis of TRM remain unclear. Exploiting a dual-screening platform integrating computational and RNAi in vivo screening approaches, we have identified transcriptional regulators of TRM differentiation. This strategy revealed numerous transcription factors with indispensable roles in TRM differentiation and homeostasis. Further, we show that tumor infiltrating lymphocytes (TIL) share a core TRM transcriptional signature, and that these factors control TIL residency. These results provide novel insight into the biology of T cell residency, which could be leveraged to enhance vaccine efficacy or adoptive therapy treatments against cancer. Disclosures No relevant conflicts of interest to declare.

Although it is known that interleukin-7 (IL-7) and IL-15 influence the survival and turnover of CD8+ T cells, less is known about how these cytokines affect different subsets during the course of the immune response. We find that IL-7 and IL-15 differentially regulate CD8+ T-cell subsets defined by KLRG1 and CD127 expression during the contraction phase of the immune response. The provision of IL-15, or the related cytokine IL-2, during contraction led to the preferential accumulation of KLRG1hiCD127lo CD8+ T cells, whereas provision of IL-7 instead favored the accumulation of KLRG1loCD127hi cells. While IL-7 and IL-15 both induced proliferation of KLRG1lo cells, KLRG1hi cells exhibited an extraordinarily high level of resistance to cytokine-driven proliferation in vivo despite their dramatic accumulation upon IL-15 administration. These results suggest that IL-15 and IL-2 greatly improve the survival of KLRG1hi CD8+ T cells, which are usually destined to perish during contraction, without inducing proliferation. As the availability of IL-15 and IL-2 is enhanced during periods of extended inflammation, our results suggest a mechanism in which a population of cytokine-dependent KLRG1hi CD8+ T cells is temporarily retained for improved immunity. Consideration of these findings may aid in the development of immunotherapeutic strategies against infectious disease and cancer.