CD8 T-cell ability to exert immunodomination correlates with T-cell receptor: Epitope association rate

Abstract

When presented alone, H7 a and HY antigens elicit CD8 T-cell responses of similar amplitude, but H7 a totally abrogates the response to HY when both antigens are presented on the same antigen-presenting cell. We found that H7a- and HY-specific T-cell precursors had similar frequencies in nonimmune mice and expressed similar levels of CD5. The H7a -specific CD8 T-cell repertoire harvested at the time of primary response showed highly restricted T-cell receptor (TCR) diversity. Furthermore, T cells specific for H7a and HY expressed equivalent levels of CD8 and TCR and displayed similar tetramer decay rates. The key difference was that anti-H7a T cells exhibited a much more rapid TCR:epitope on-rate than anti-HY T cells. Coupled with evidence that primed CD8 T cells limit the duration of antigen presentation by killing or inactivating antigen-presenting cells, our data support a novel and simple model for immunodomination: the main feature of T cells that exert immunodomination is that, compared with other T cells, they are functionally primed after a shorter duration of antigen presentation.

Asynchronous Differentiation of CD8 T Cells That Recognize Dominant and Cryptic Antigens

“…We reported that H7 a -and HY-specific T cell precursors have similar frequencies in nonimmune mice, and that H7 a -specific CD8 T cells harvested at the time of primary response show highly restricted TCR diversity (23). Thus, the immunodominant status of H7 a is not a question of T cell precursor frequency or TCR diversity.…”

“…4A). Because the frequencies of anti-H7 a and anti-HY T cell precursors in the preimmune repertoire are similar (23), anti-H7 a T cells underwent more extensive expansion than anti-HY T cells. The salient finding though was the lack of synchronicity between expansion of the two T cell populations.…”

“…Two studies reported that injection of very large numbers of memory CD8 T cells specific for immunodominated Ag did not enable these T cells to compete more successfully against T cells that recognized dominant epitopes (14,24). Thus, except perhaps in some extreme situations, dominating T cells do not win the competition at the T cell/APC interface because they are more abundant than other T cell clonotypes in preimmune animals (23). Dominating T cells win the competition because they possess some elusive functional advantage over other T cells (14,19,23).…”

“…Several nonmutually exclusive explanations have been proposed for this. Dominating T cells may kill or exhaust APCs, monopolize APC resources, or directly send inhibitory signals to nondominant T cells (7,15,19,22,23). Two studies reported that injection of very large numbers of memory CD8 T cells specific for immunodominated Ag did not enable these T cells to compete more successfully against T cells that recognized dominant epitopes (14,24).…”

“…Thus, except perhaps in some extreme situations, dominating T cells do not win the competition at the T cell/APC interface because they are more abundant than other T cell clonotypes in preimmune animals (23). Dominating T cells win the competition because they possess some elusive functional advantage over other T cells (14,19,23).…”