Uncoupling of Proliferative Potential and Gain of Effector Function by CD8+ T Cells Responding to Self-Antigens

Abstract

Professional antigen-presenting cells (APCs) are capable of transporting self-antigens from peripheral tissues to secondary lymphoid organs where they are presented to potentially autoreactive CD8+ T cells. In the absence of an inflammatory response, this results in immune tolerance. The presence of activated, antigen-specific CD4+ T cells converts this tolerogenic encounter into an immunogenic one by promoting extensive proliferation of CD8+ T cells and their development into effectors. Surprisingly, activation of APCs with an agonistic antibody specific for CD40 could not substitute for CD4+ help in this task. Anti-CD40 induced recruitment of dendritic cells expressing high levels of B7 costimulatory molecules into the lymph nodes, which in turn, greatly enhanced activation and expansion of CD8+ T cells. However, these activated CD8+ cells did not demonstrate effector function. We conclude that proliferative potential and gain of effector function are separable events in the differentiation program of CD8+ T cells.

Subversion of effector CD8+ T cell differentiation in acute hepatitis C virus infection: the role of the virus

“…3c). Therefore, the presence of HCVcore during the initial activation of memory cells (and possibly the priming of naive cells) induces a dichotomy between the expansion and the differentiation of these cells, affecting only the latter and supporting the view that expansion and differentiation of memory cells can be two dissociated events [11,12,17].…”

“…The sustained antigenic stimulation in our in vitro system might, however, hide the further option that in vivo CTL priming is impaired, because circulating HCVcore may affect professional APC (i.e. DC), leading to CTL expansion, but impaired effector differentiation [8][9][10][11][12][13][14][15][16][17][42][43][44].…”

“…A successful CTL response is dependent on a wide array of stimulatory signals present during priming, such as those provided by professional APC, duration of antigenic stimulus, CD4 help, and the type of cytokines [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Efficient simultaneous signals (or such compensating among themselves) are mandatory for maintaining long-term central memory CCR7 + cells proliferating even in the absence of antigen (that is, in response to homeostatic cytokines), and differentiating in full CCR7 -effector cells, upon a possible re-encounter with the antigen [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19].…”

“…Efficient simultaneous signals (or such compensating among themselves) are mandatory for maintaining long-term central memory CCR7 + cells proliferating even in the absence of antigen (that is, in response to homeostatic cytokines), and differentiating in full CCR7 -effector cells, upon a possible re-encounter with the antigen [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. By contrast, subthreshold signal levels may provide different scenarios ranging from anergy to a high expansion of memory cells that are devoid of effector functions [10][11][12][13][14][15][16][17][18][19][20]. The signals governing the strength of CTL activation can be deeply affected by the intervention of different mechanisms of immune subversion established by several viruses, known to interact with CTL development [21].…”

Subversion of effector CD8+ T cell differentiation in acute hepatitis C virus infection: exploring the immunological mechanisms

“…Central memory cells express CCR7 and CD62L enabling homing to peripheral lymphoid tissues, where they promptly proliferate in response to antigen, generating a large expansion of effector memory cells, which in turn migrate into inflamed tissues, upon CCR7 and CD62L down-regulation [3,[6][7][8][9]. The success of a CTL priming is dependent on efficient and sustained signals such as those provided by professional APC, duration of antigenic stimulation, CD4 help, and the type of cytokine milieu [10][11][12][13][14][15][16][17][18][19]. By contrast, the lack or the defective performance of one or more of these signals may evolve into different scenarios ranging from abortive CTL divisions (tolerance) to a high expansion of memory cells that are devoid of effector functions [10][11][12][13][14][15][16][17][18][19][20].…”