Narrowing the Gap: Preserving Repertoire Diversity Despite Clonal Selection during the CD4 T Cell Response

Abstract

T cell immunity relies on the generation and maintenance of a diverse repertoire of T cell antigen receptors (TCRs). The strength of signaling emanating from the TCR dictates the fate of T cells during development, as well as during the immune response. Whereas development of new T cells in the thymus increases the available TCR repertoire, clonal selection during the immune response narrows TCR diversity through the outgrowth of clonotypes with the fittest TCR. To ensure maintenance of TCR diversity in the antigen-selected repertoire, specific mechanisms can be envisaged that facilitate the participation of T cell clonotypes with less than best fit TCRs. Here, we summarize the evidence for the existence of such mechanisms that can prevent the loss of diversity. A number of T cell-autonomous or extrinsic factors can reverse clonotypic hierarchies set by TCR affinity for given antigen. Although not yet complete, understanding of these factors and their mechanism of action will be critical in interventional attempts to mold the antigen-selected TCR repertoire.

Keywords: CD4 T cell; T cell response; TCR affinity; TCR repertoire; clonotypic diversity.

Figure 1

A T cell’s behavior depends on the preimmune repertoire composition. A given clonotype (depicted in gray) with relatively low TCR affinity for the immunizing antigen will either fail to expand (in the presence of higher affinity competitors, Host 1), or participate in the response (when competition is weaker, Host 2).

Figure 2

Antigen-selected repertoire composition according to response kinetics. The high-affinity clonotype (depicted in red) will begin clonal expansion earlier than the low-affinity one (depicted in blue) as it is more sensitive to initially low antigen concentration during an infection. Clonal expansion will cease when eight antigen-reactive cells are produced (race finish). (A) When the lag-time between recruitment of the high- and low-affinity clonotypes is longer than time to expansion of high-affinity clonotype to eight cells, the response will comprise entirely of high-affinity progeny. This may arise when antigenic pMHCII is distributed over many APCs, each presenting at low density. Even though the threshold for activation of the low-affinity clonotype is eventually crossed, its expansion is actively suppressed (race is finished). (B) When the lag-time in recruitment is shorter than the time is takes to complete the race (in the case low precursor frequency or when antigen is sharply introduced and highly concentrated on few APCs), the final eight cells will contain a proportion of low-affinity progeny.

Figure 3

The balance of reactivity to self or antigen pMHCII complexes. The TCR of a given T cell may have high (red) or low (blue) affinity for self pMHCII (left side of the cell) or a particular antigenic pMHCII complex (right side of the cell). High affinity to either of these contributes positively to clonal expansion. (A) When all four possible (simplified) combinations are present, the clonotype that combines high affinity for self and for antigenic pMHCII will prevail. Selection of such clonotypes from large enough repertoires may create the impression that high affinity to self and antigen are positively correlated. (B) Between two clonotypes with equal affinity to self, the one with higher affinity to antigen will prevail. (C) Between two clonotypes with equal affinity to antigen, the one with higher affinity to self will prevail. (D) The outcome of competition between clonotypes one of which is high affinity for self and the other for antigen is currently difficult to predict.