Many intracellular pathogens infect a broad range of host tissues, but the importance of T cells for immunity in these sites is unclear because most of our understanding of antimicrobial T cell responses comes from analyses of lymphoid tissue. Here, we show that in response to viral or bacterial infection, antigen-specific CD8 T cells migrated to nonlymphoid tissues and were present as long-lived memory cells. Strikingly, CD8 memory T cells isolated from nonlymphoid tissues exhibited effector levels of lytic activity directly ex vivo, in contrast to their splenic counterparts. These results point to the existence of a population of extralymphoid effector memory T cells poised for immediate response to infection.

The naïve and memory T lymphocyte pools are maintained through poorly understood homeostatic mechanisms that may include signaling via cytokine receptors. We show that interleukin-7 (IL-7) plays multiple roles in regulating homeostasis of CD8+ T cells. We found that IL-7 was required for homeostatic expansion of naïve CD8+ and CD4+ T cells in lymphopenic hosts and for CD8+ T cell survival in normal hosts. In contrast, IL-7 was not necessary for growth of CD8+ T cells in response to a virus infection but was critical for generating T cell memory. Up-regulation of Bcl-2 in the absence of IL-7 signaling was impaired after activation in vivo. Homeostatic proliferation of memory cells was also partially dependent on IL-7. These results point to IL-7 as a pivotal cytokine in T cell homeostasis.

Evidence has accumulated that cytokines have a fundamental role in the differentiation of memory T cells. Here, we follow the CD8+ T cell from initial activation to memory-cell generation, indicating the checkpoints at which cytokines determine the fate of the T cell. Members of the common cytokine-receptor gamma-chain (gammac)-cytokine family--in particular, interleukin-7 (IL-7) and IL-15--act at each stage of the immune response to promote proliferation and survival. In this manner, a stable and protective, long-lived memory CD8+ T-cell pool can be propagated and maintained.

We identify here a new class of lung tissue-resident memory CD4 T cells which exhibit tissue tropism and retention independent of antigen or inflammation. Tissue-resident memory CD4 T cells in the lung did not circulate or emigrate from the lung in parabiosis experiments, were protected from in vivo antibody labeling, and expressed elevated levels CD69 and CD11a compared to circulating memory populations. Importantly, influenza-specific lung-resident memory CD4 T cells served as in situ protectors to respiratory viral challenge, mediating enhanced viral clearance and survival to lethal influenza infection. By contrast, memory CD4 T cells isolated from spleen recirculated among multiple tissues without retention, and failed to mediate protection to influenza infection, despite their ability to expand and migrate to the lung. Our results reveal tissue compartmentalization as a major determining factor for immune-mediated protection in a key mucosal site, important for targeting local protective responses in vaccines and immunotherapies.

Through genetic recombination, the adaptive immune system generates a diverse T cell repertoire allowing recognition of a vast spectrum of foreign antigens. Any given CD8+ T cell specificity is thought to be rare, but none have been directly quantified. Here, major histocompatibility complex tetramer and magnetic-bead technology were coupled to quantitate naive antigen-specific CD8+ T cells and the early response to infection. Among six specificities measured, the number of naive antigen-specific precursors ranged from approximately 80 to 1200 cells/mouse. After vesicular stomatitis virus infection, the antigen-specific CD8+ T cell response occurred in discrete phases: prolonged activation of a subset of cells over the first 72 hr followed by a rapid proliferative burst. Naive precursor frequency altered response kinetics and regulated immunodominance, as well as the time required for the responding population to shift toward CD62L(hi) memory cells. Thus, initial endogenous precursor frequencies were surprisingly diverse and not only regulated initial immune response characteristics but also controlled memory CD8+ T cell lineage decisions.