Memory T cells count their ancestors

Although it is well established that there are two memory T-cell populations — central memory T (T_CM) cells and effector memory T (T_EM) cells — which can be identified by distinct homing characteristics and effector functions, it is not clear whether these are distinct lineages or whether the development of one subset depends on the other. New data published in Nature Immunology now indicate that the naive T-cell precursor frequency determines which of these developmental schemes occurs.

T_CM cells express CC-chemokine receptor 7 (CCR7) and CD62L, and are found in lymphoid organs. By contrast, T_EM cells do not express either CCR7 or CD62L, and they reside in non-lymphoid tissues and mediate effector functions immediately after activation. Previous studies have led to the emergence of three models of memory T-cell differentiation: first, that T_CM cells are a continual source of T_EM cells; second, that T_CM and T_EM cells are distinct lineages; and third, that, over time, T_EM cells convert to T_CM cells. To further investigate the relationship between T_CM and T_EM cells, Marzo et al. assessed the phenotypic stability of T_CM and T_EM cells (defined as CD62L^hi and CD62L^low, respectively) after transferring the cells to separate naive recipients. When the transferred memory T-cell subsets were isolated from mice that were infected with ovalbumin-expressing vesicular stomatitis virus (VSV-OVA) and that had previously been recipients of naive CD8⁺ T cells expressing the OT-I T-cell receptor (OT-I TCR; which is specific for a peptide derived from OVA), the T_CM cells remained CD62L^hi, whereas almost half of the T_EM cells converted to T_CM cells. By contrast, when polyclonal OVA-specific CD8⁺ memory T-cell subsets were isolated from wild-type mice infected with VSV-OVA, both T_CM and T_EM cells maintained their original phenotype. Consistent with a role for naive T-cell precursor frequency in determining CD8⁺ memory T-cell phenotype, if the number of naive CD8⁺OT-I TCR⁺ T cells transferred to mice that were subsequently infected with VSV-OVA was markedly decreased, then OVA-specific T_EM cells did not convert to T_CM cells when transferred to secondary recipients.

These data have led the authors to suggest that memory T-cell differentiation fits different models depending on the initial frequency of naive precursors: a high initial frequency of naive precursors leads to the development of T_CM cells, T_EM cells and a population of CD62L^low cells (that is, cells that are phenotypically T_EM cells) that can convert to T_CM cells, whereas a low initial frequency of naive precursors, such as occurs physiologically, leads to the development of T_CM cells and T_EM cells as distinct lineages.