Strength of Stimulus and Clonal Competition Impact the Rate of Memory CD8 T Cell Differentiation

Abstract

The developmental pathways of long-lived memory CD8 T cells and the lineage relationship between memory T cell subsets remain controversial. Although some studies indicate the two major memory T cell subsets, central memory T (TCM) and effector memory T (TEM), are related lineages, others suggest that these subsets arise and are maintained independently of one another. In this study, we have investigated this issue and examined the differentiation of memory CD8 T cell subsets by tracking the lineage relationships of both endogenous and TCR transgenic CD8 T cell responses after acute infection. Our data indicate that TCR transgenic as well as nontransgenic TEM differentiate into TCM in the absence of Ag. Moreover, the rate of memory CD8 T cell differentiation from TEM into the self-renewing and long-lived pool of TCM is influenced by signals received during priming, including Ag levels, clonal competition, and/or the duration of infection. Although some TEM appear to not progress to TCM, the vast majority of TCM are derived from TEM. Thus, long-lasting, Ag-independent CD8 T cell memory results from progressive differentiation of memory CD8 T cells, and the rate of memory T cell differentiation is governed by events occurring early during T cell priming.

IL-12 Signaling Drives CD8+ T Cell IFN-γ Production and Differentiation of KLRG1+ Effector Subpopulations during Toxoplasma gondii Infection

“…Currently, it is not yet settled whether re-expression of CD62L in activated T cells occurs in vivo. In an adoptive transfer system using physiologically appropriate numbers of TCR transgenic T cells, conversion of effector memory T cells (T EM ) to central memory T cells (T CM ) cells by re-expression of CD62L was not observed (54), whereas in a recent paper CD62L reacquisition by a polyclonal population of antiviral effector CTLs was reported (55). Given this uncertainty, we favor the scenario that most FIV CD8 ϩ T cells probably give rise to the dominant, terminal FIII subpopulation.…”

Differentiation of Central Memory CD8 T Cells Is Independent of CD62L-Mediated Trafficking to Lymph Nodes

“…After acute infections, the percentage of memory T cells with central memory phenotype increases steadily over time. Although the exact reasons for this observation are still a matter of debate (18,32,33), one possible explanation is the previously demonstrated capability of central memory T cells to undergo more rapid basal proliferation compared with effector memory T cells (18). Whether this accelerated proliferation is related to the lymph node environment or an intrinsic property of central memory T cells is unclear.…”

Memory T Cells are Uniquely Resistant to Melanoma-induced Suppression

“…Following expansion, acutely activated T cell populations enter a phase of programmed contraction, during which the vast majority of antigen-specific shortlived effector T cells undergo apoptotic cell death. A small subset of memory precursor effector T cells survive contraction and eventually differentiate into memory T cells capable of long-term survival, even in the absence of antigenic stimulation [1][2][3][4][5][6]. We have previously found that a critical window of in vivo interaction exists between resting T cells and growing tumors, after which resting T cells are no longer capable of maximal proliferative expansion in response to antigenic stimulation.…”

“…The size of a memory T cell population is a function of the clonal burst size of T cells present at the moment of maximal proliferative expansion and the rate of apoptotic contraction that takes place thereafter; by negatively impacting both of these variables, the suppressive influence of melanoma would be expected to markedly impair the generation of new T cell memory [3][4][5][6]. We previously observed significantly smaller numbers of LCMV-specific MPECs 10 days after viral infection; in the present analysis, we confirmed that there are markedly smaller numbers of LCMV-specific memory T cells present 26 days after viral infection [18].…”

“…After clonal expansion, activated T cells enter a phase of rapid contraction, during which the vast majority of short-lived effector T cells undergo apoptotic cell death. A small subset of memory precursor effector T cells (MPEC) survives contraction and eventually differentiates into memory T cells, which are capable of prolonged homeostatic proliferation and rapid expansion in response to repeat exposure to their cognate antigen [1][2][3][4][5][6]. The ability to identify and expand large populations of activated CD8+ T cells specific for cancer antigens has motivated great interest in the use of adoptive cell transfer as a novel means of treating cancer [7][8][9][10][11][12][13][14].…”