CD44loCD62Lhi regulatory T cells preferentially access IL-2 in T cell zones due to expression of CCR7

Memory T cells can be divided into central memory T cell (T CM cell) and effector memory T cell (T EM cell) subsets based on homing characteristics and effector functions. Whether T EM and T CM cells represent interconnected or distinct lineages is unclear, although the present paradigm suggests that T EM and T CM cells follow a linear differentiation pathway from naive T cells to effector T cells to T EM cells to T CM cells. We show here that naive T cell precursor frequency profoundly influenced the pathway along which CD8 + memory T cells developed. At low precursor frequency, those T EM cells generated represented a stable cell lineage that failed to further differentiate into T CM cells. These findings do not adhere to the present dogma regarding memory T cell generation and provide a means for identifying factors controlling memory T cell lineage commitment.Based on homing characteristics and effector functions, at least two types of memory T cells have been described in CD4 + and CD8 + T cell populations. The original descriptions of central and effector memory T cells suggested that central memory T cells (T CM cells) reside in lymphoid organs and express CCR7 and CD62L, whereas effector memory T cells (T EM cells) reside mainly in nonlymphoid tissues, do not express CCR7 or CD62L and have immediate effector functions 1-3 . This raised the question of how T CM cells and T EM cells are generated and whether each is the product of interdependent or separate lineages.Three models of differentiation have been proposed, with the first being that T CM cells provide a continual source of T EM cells. This model is based on the findings that memory CCR7 + T cells in short-term in vitro culture can lose expression of this chemokine receptor and in the process become functionally competent1 ,4 . Analysis of the T cell receptor (TCR) repertoire of human blood memory CD8 + T cells has suggested an additional possibility in which T CM and T EM cells represent mostly separate lineages 5 . In contrast, an alternative model has indicated that over time T EM cells convert to T CM cells 6 . This conclusion was derived from analysis of TCR-transgenic CD8 + memory T cells specific for lymphocytic choriomeningitis virus (LCMV) glycoprotein 33 (gp33) that had been separated by virtue of

Memory T cells are distributed throughout the body following infection, but the migratory dynamics of the memory pool in vivo is unknown. The ability of circulating microbe-specific memory T cells to populate lymphoid and nonlymphoid tissues was examined using adoptive transfer and parabiosis systems. While migration of memory CD8 T cells to lymph nodes and peritoneal cavity required G(i)-coupled receptor signaling, migration to the spleen, bone marrow, lung, and liver was independent of this pathway. Following parabiosis, memory T cells rapidly equilibrated into the lymphoid tissues, lung, and liver of each parabiont, implying most memory cells were not obligately tissue resident. Equilibration of memory cell populations was delayed in the brain, peritoneal cavity, and intestinal lamina propria, indicating controlled gating for entry into these tissues. In addition, memory cell migration to the lamina propria required beta7 integrins. Thus, the blood-borne T cell pool serves to maintain the homeostasis of tissue-based memory populations.

Activated virus-specific CD8 T cells remain in the lung airways for several months after influenza virus infection. We show that maintenance of this cell population is dependent upon the route of infection and prolonged presentation of viral antigen in the draining lymph nodes (DLN) of the respiratory tract. The local effects on T cell migration have been examined. We show retention of virus-specific CD8 T cells in the mediastinal lymph node (MLN) and continuing recruitment of blood-borne migrants into the lung airways during antigen presentation. These data show that antigen that is retained after pulmonary influenza virus infection controls the migratory pattern and activation state of virus-specific CD8 T cells near the site of virus amplification.

Secondary lymphoid organs (SLOs) promote primary immune responses by recruiting naive lymphocytes and activated APCs. However, their role in the persistence or responsiveness of memory lymphocytes is unclear. We tested whether memory cells were maintained and could respond to challenge in the absence of SLOs. We found that influenza-specific CD8 cells in the lung acquired a memory phenotype, underwent homeostatic proliferation, recirculated through nonlymphoid tissues, and responded to and cleared a challenge infection in the complete absence of SLOs. Similarly, influenza-specific virus-neutralizing antibody was generated and maintained in the absence of SLOs. Inducible bronchus-associated lymphoid tissue (iBALT) was also formed in the lungs of previously infected mice and may provide a niche for the maintenance of memory cells at the local level. These data show that SLOs are dispensable for the maintenance of immunologic memory and directly demonstrate the utility of local tissues, such as iBALT, in secondary immune responses.