Recruitment of Antigen-Specific CD8 ⁺ T Cells in Response to Infection Is Markedly Efficient

Abstract

The magnitude of antigen-specific CD8+ T cell responses is not fixed but correlates with the severity of infection. Although by definition T cell response size is the product of both the capacity to recruit naïve T cells (clonal selection) and their subsequent proliferation (clonal expansion), it remains undefined how these two factors regulate antigen-specific T cell responses. We determined the relative contribution of recruitment and expansion by labeling naïve T cells with unique genetic tags and transferring them into mice. Under disparate infection conditions with different pathogens and doses, recruitment of antigen-specific T cells was near constant and close to complete. Thus, naïve T cell recruitment is highly efficient, and the magnitude of antigen-specific CD8+ T cell responses is primarily controlled by clonal expansion.

A Mechanism for TCR Sharing between T Cell Subsets and Individuals Revealed by Pyrosequencing

“…The presence of those same TCRb clonotypes in the naive pool would then derive from thymic replenishment of the naive repertoire with identical TCR sequences. Indeed, recent studies in mice showed that, although governed by affinity for peptide-MHC (11,41), recruitment of Ag-specific CD8 + T cells from the naive pool is markedly efficient (9). This scenario is supported by our observations that TCRb clonotypes common to the memory and naive pools tended to have larger sizes in both pools and are more efficiently generated by convergent recombination.…”

“…Yet, this approach should be considered in light of the dynamic relationship between these two populations, which involves continuous thymic output of new naive T cells, homeostatic maintenance of the peripheral repertoire, and recruitment of naive T cells to the memory pool through episodic and persistent antigenic stimulation (7,8). Recruitment from the naive T cell pool seems to be highly efficient (9), such that even CD8 + T cell clonotypes with very low avidity for cognate Ag (10,11) are mobilized from the naive repertoire. Therefore, one might expect that the clonotypic landscape of the memory T cell repertoire after initial recruitment should reflect the hierarchical distribution of available clonotypes within the naive T cell repertoire.…”

Primary CTL response magnitude in mice is determined by the extent of naive T cell recruitment and subsequent clonal expansion

“…The focus to date has, however, been on the more prominent pMHCI-specific CTL sets, with the implication being that all the naive CTLps are recruited into the immune response. This is also the conclusion of a recent study that tracked recruitment of genetically tagged TCR Tg T cells after transfer (17). But is that indeed the case in a polyclonal T cell response to viral infection, and is CTLp prevalence the overarching determinant of CTL response magnitude?…”

Affinity Thresholds for Naive CD8+ CTL Activation by Peptides and Engineered Influenza A Viruses

“…Efficient recruitment into and survival through an immune response requires that responding T cells achieve a necessary level of "fitness" by crossing various signaling thresholds (3,5). The primary measure of such molecular "fitness" is considered to be the strength of TCR/ pMHCI binding (6), which determines the differential selection of naive precursors into an immune response (7)(8)(9), the spectrum of subsequent clonal expansion and extent of differentiation to effector/memory status (6,9). What constitutes optimal, or even sufficient, TCR/pMHCI affinity/avidity is, however, a matter of debate, with different conclusions being reached from a variety of in vivo and in vitro approaches using altered peptide ligands (APLs) (4,(9)(10)(11)(12)(13)(14).…”