RESUMEN
Skin-resident CD8+ T cells include distinct interferon-γ-producing [tissue-resident memory T type 1 (TRM1)] and interleukin-17 (IL-17)-producing (TRM17) subsets that differentially contribute to immune responses. However, whether these populations use common mechanisms to establish tissue residence is unknown. In this work, we show that TRM1 and TRM17 cells navigate divergent trajectories to acquire tissue residency in the skin. TRM1 cells depend on a T-bet-Hobit-IL-15 axis, whereas TRM17 cells develop independently of these factors. Instead, c-Maf commands a tissue-resident program in TRM17 cells parallel to that induced by Hobit in TRM1 cells, with an ICOS-c-Maf-IL-7 axis pivotal to TRM17 cell commitment. Accordingly, by targeting this pathway, skin TRM17 cells can be ablated without compromising their TRM1 counterparts. Thus, skin-resident T cells rely on distinct molecular circuitries, which can be exploited to strategically modulate local immunity.
Asunto(s)
Linfocitos T CD8-positivos , Memoria Inmunológica , Células T de Memoria , Piel , Linfocitos T CD8-positivos/inmunología , Células T de Memoria/inmunología , Piel/inmunología , Humanos , Células Th17/inmunología , Ligando Coestimulador de Linfocitos T Inducibles/metabolismo , Proteínas Proto-Oncogénicas c-maf/metabolismo , Interleucina-7/metabolismoRESUMEN
Tissue-resident memory T (TRM ) cells play a vital role in local immune protection against infection and cancer. The location of TRM cells within peripheral tissues at sites of pathogen invasion allows for the rapid detection and elimination of microbes, making their generation an attractive goal for the development of next-generation vaccines. Here, we discuss differential requirements for CD8+ TRM cell development across tissues with implications for establishing local prophylactic immunity, emphasizing the role of tissue-derived factors, local antigen, and adjuvants on TRM cell generation in the context of vaccination.
Asunto(s)
Linfocitos T CD8-positivos , Vacunas , Humanos , Memoria Inmunológica , Sistema Inmunológico , VacunaciónRESUMEN
Tissue-resident memory T (TRM) cells provide long-lasting immune protection. One of the key events controlling TRM cell development is the local retention of TRM cell precursors coupled to downregulation of molecules necessary for tissue exit. Sphingosine-1-phosphate receptor 5 (S1PR5) is a migratory receptor with an uncharted function in T cells. Here, we show that S1PR5 plays a critical role in T cell infiltration and emigration from peripheral organs, as well as being specifically downregulated in TRM cells. Consequentially, TRM cell development was selectively impaired upon ectopic expression of S1pr5, whereas loss of S1pr5 enhanced skin TRM cell formation by promoting peripheral T cell sequestration. Importantly, we found that T-bet and ZEB2 were required for S1pr5 induction and that local TGF-ß signaling was necessary to promote coordinated Tbx21, Zeb2, and S1pr5 downregulation. Moreover, S1PR5-mediated control of tissue residency was conserved across innate and adaptive immune compartments. Together, these results identify the T-bet-ZEB2-S1PR5 axis as a previously unappreciated mechanism modulating the generation of tissue-resident lymphocytes.
Asunto(s)
Diferenciación Celular/genética , Tejido Linfoide/metabolismo , Células T de Memoria/metabolismo , Receptores de Esfingosina-1-Fosfato/genética , Linfocitos T/metabolismo , Animales , Linfocitos T CD8-positivos/metabolismo , Movimiento Celular/genética , Células Cultivadas , Perfilación de la Expresión Génica/métodos , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , RNA-Seq/métodos , Receptores de Esfingosina-1-Fosfato/metabolismo , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/genética , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/metabolismoRESUMEN
Current immunotherapies involving CD8+ T cell responses show remarkable promise, but their efficacy in many solid tumors is limited, in part due to the low frequency of tumor-specific T cells in the tumor microenvironment (TME). Here, we identified a role for host atypical chemokine receptor 4 (ACKR4) in controlling intratumor T cell accumulation and activation. In the absence of ACKR4, an increase in intratumor CD8+ T cells inhibited tumor growth, and nonhematopoietic ACKR4 expression was critical. We show that ACKR4 inhibited CD103+ dendritic cell retention in tumors through regulation of the intratumor abundance of CCL21. In addition, preclinical studies indicate that ACKR4 and CCL21 are potential therapeutic targets to enhance responsiveness to immune checkpoint blockade or T cell costimulation.