CD8 tissue-resident memory T (TRM) cells provide frontline protection at barrier tissues; however, mechanisms regulating TRM cell development are not completely understood. Priming dictates the migration of effector T cells to the tissue, while factors in the tissue induce in situ TRM cell differentiation. Whether priming also regulates in situ TRM cell differentiation uncoupled from migration is unclear. Here, we demonstrate that T cell priming in the mesenteric lymph nodes (MLN) regulates CD103+ TRM cell differentiation in the intestine. In contrast, T cells primed in the spleen were impaired in the ability to differentiate into CD103+ TRM cells after entry into the intestine. MLN priming initiated a CD103+ TRM cell gene signature and licensed rapid CD103+ TRM cell differentiation in response to factors in the intestine. Licensing was regulated by retinoic acid signaling and primarily driven by factors other than CCR9 expression and CCR9-mediated gut homing. Thus, the MLN is specialized to promote intestinal CD103+ CD8 TRM cell development by licensing in situ differentiation.

CD8 tissue-resident memory T (T_RM) cells primarily reside in nonlymphoid tissues without recirculating and provide front-line protective immunity against infections and cancers. CD8 T_RM cells can be generally divided into CD69⁺ CD103⁻ T_RM cells (referred to as CD103⁻ T_RM cells) and CD69⁺ CD103⁺ T_RM cells (referred to as CD103⁺ T_RM cells). TGF-β plays a critical role in the development and maintenance of CD103⁺ CD8 T_RM cells. In this review, we summarize the current understanding of tissue-specific activation of TGF-β mediated by integrins and how it contributes to CD103⁺ CD8 T_RM cell development and maintenance. Furthermore, we discuss the underlying mechanisms utilized by TGF-β to regulate the development and maintenance of CD103⁺ CD8 T_RM cells. Overall, this review highlights the importance of TGF-β in regulating this unique subset of memory CD8 T cells that may shed light on improving vaccine design to target this population.

Listeria monocytogenes (Lm) infection induces robust CD8 T cell responses, which play a critical role in resolving Lm during primary infection and provide protective immunity to re-infections. Comprehensive studies have been conducted to delineate the CD8 T cell response after Lm infection. In this review, the generation of the CD8 T cell response to Lm infection will be discussed. The role of dendritic cell subsets in acquiring and presenting Lm antigens to CD8 T cells and the events that occur during T cell priming and activation will be addressed. CD8 T cell expansion, differentiation and contraction as well as the signals that regulate these processes during Lm infection will be explored. Finally, the formation of memory CD8 T cell subsets in the circulation and in the intestine will be analyzed. Recently, the study of CD8 T cell responses to Lm infection has begun to shift focus from the intravenous infection model to a natural oral infection model as the humanized mouse and murinized Lm have become readily available. Recent findings in the generation of CD8 T cell responses to oral infection using murinized Lm will be explored throughout the review. Finally, CD8 T cell-mediated protective immunity against Lm infection and the use of Lm as a vaccine vector for cancer immunotherapy will be highlighted. Overall, this review will provide detailed knowledge on the biology of CD8 T cell responses after Lm infection that may shed light on improving rational vaccine design.

The basic leucine zipper transcription factor ATF-like 3 (BATF3) is required for the development of conventional type 1 dendritic cells that are essential for cross-presentation and CD8 T cell–mediated immunity against intracellular pathogens and tumors. However, whether BATF3 intrinsically regulates CD8 T cell responses is not well studied. In this article, we report a role for cell-intrinsic Batf3 expression in regulating the establishment of circulating and resident memory T cells after foodborne Listeria monocytogenes infection of mice. Consistent with other studies, Batf3 expression by CD8 T cells was dispensable for the primary response. However, Batf3−/− T cells underwent increased apoptosis during contraction to contribute to a substantially reduced memory population. Batf3−/− memory cells had an impaired ability to mount a robust recall response but remained functional. These findings reveal a cell-intrinsic role of Batf3 in regulating CD8 T cell memory development.

FTY720 is a treatment for relapsing remitting multiple sclerosis (MS). It is an analog of sphingosine-1-phosphate (S1P) and targets S1P receptors 1, 3, 4, and 5. Recent reports indicate an association between long-term exposure to FTY720 and cases of cryptococcal infection. Here, we studied the effect of FTY720 and its derivative, BAF312, which only target S1P receptors 1 and 5, in a mouse model of cryptococcal infection. We found that treatment with FTY720, but not with BAF312, led to decreased survival and increased organ burden in mouse cryptococcal granulomas. Both FTY720 and BAF312 caused a profound CD4⁺ and CD8⁺ T cell depletion in blood and lungs but only treatment with FTY720 led to cryptococcal reactivation. Treatment with FTY720, but not with BAF312, was associated with disorganization of macrophages and with M2 polarization at the granuloma site. In a cell system, FTY720 decreased phagocytosis and production of reactive oxygen species by macrophages, a phenotype recapitulated in the S1pr3^–/– knockout macrophages. Our results suggest that FTY720 reactivates cryptococcosis from the granuloma through a S1P receptor 3–mediated mechanism and support the rationale for development of more-specific receptor modulators for therapeutic use of MS.

Yersinia pseudotuberculosisis a foodborne pathogen that subverts immune function by translocation ofYersiniaouter protein (Yop) effectors into host cells. As adaptive γδ T cells protect the intestinal mucosa from pathogen invasion, we assessed whetherY.pseudotuberculosissubverts these cells in mice and humans. Tracking Yop translocation revealed that the preferential delivery of Yop effectors directly into murine Vγ4 and human Vδ2⁺T cells inhibited anti-microbial IFNγ production. Subversion was mediated by the adhesin YadA, injectisome component YopB, and translocated YopJ effector. A broad anti-pathogen gene signature and STAT4 phosphorylation levels were inhibited by translocated YopJ. Thus,Y.pseudotuberculosisattachment and translocation of YopJ directly into adaptive γδ T cells is a major mechanism of immune subversion in mice and humans. This study uncovered a conservedY.pseudotuberculosispathway that subverts adaptive γδ T cell function to promote pathogenicity.