In response to infection, CD8 T cells are activated by inflammation and foreign antigen and expand exponentially in number, develop effector functions that enable pathogen clearance, and then contract to form immunological memory. A subset of memory CD8 T cells, designated tissue-resident CD8 T cells (TRM), reside permanently in non-lymphoid tissue and provide critical protection at barrier sites in the event of reinfection. The fundamental processes that control the emergence of TRM are not fully understood. We propose that expression of receptors that mediate T cell interactions with extracellular matrix microenvironments in nonlymphoid tissue plays a critical role in TRM differentiation. Since the collagen-binding integrin ?1?1 has been identified on TRM, we examined the response of ?1 integrin deficient T cells following viral challenge. While CD8 T cell expression of ?1?1 integrin is not required for initial T cell activation signals that lea to effector function, loss of ?1?1 enhanced the development of a long-lasting TRM phenotype in the lung parenchyma following influenza infection. Based on these findings, we hypothesize that T cell ?1?1 integrin expression inhibits the formation of tissue resident memory CD8 T cells by limiting effector phase expansion and suppressing responsiveness to TRM differentiation cues in vivo. We will test this hypothesis by tracking antigen-specific immune responses in vivo utilizing state-of-the art flow cytometry, quantitative immunofluorescence microscopy, and two-photon microscopy to complete two Specific Aims. First, we will define the requirement for ?1?1 integrin in generating TRM populations in non-lymphoid tissue. We will characterize alterations in the primary immune response of ?1 integrin deficient T cells and evaluate changes in CD8 T cell expansion, contraction, memory formation, and tissue distribution and residency using both local and systemic viral infections. Second, we will define the functional mechanism of ?1?1 integrin inhibition of TRM formation by determining the role of ?1?1 in regulating the response of effector T cells to TGF?, and the adhesion and motility of TRM in non-lymphoid tissue. This project will lead to important advances in our understanding of TRM by characterizing a novel function for ?1?1 integrin on T cells and defining a mechanism for generating increased populations of TRM in non-lymphoid tissue. These findings will aid in improving the generation of TRM following vaccination and treatment strategies for autoimmunity and inflammatory diseases.
To control infections such as influenza, the immune system generates large populations of CD8 T cells that circulate throughout body tissues and kill infected cells. When the infection is over, populations of memory CD8 T cells reside permanently as sentinels in barrier tissues, such as the lungs, and can rapidly protect the host from re-infection. This proposal will define a novel mechanism by which the local environment regulates the formation of these resident memory T cells. These findings will have important implications for improving the longevity of vaccines and therapies to target autoimmunity.
| Beura, Lalit K; Mitchell, Jason S; Thompson, Emily A et al. (2018) Intravital mucosal imaging of CD8+ resident memory T cells shows tissue-autonomous recall responses that amplify secondary memory. Nat Immunol 19:173-182 |
