Dominant Clonotypes within HIV-Specific T Cell Responses Are Programmed Death-1high and CD127low and Display Reduced Variant Cross-Reactivity

Abstract

HIV-epitope-specific T cell responses are often comprised of clonotypic expansions with distinct functional properties. In HIV+ individuals, we measured PD-1 and IL-7Rα expression, MHC-I tetramer binding, cytokine production, and proliferation profiles of dominant and sub-dominant T cell receptor clonotypes to evaluate the relationship between the composition of the HIV-specific T cell repertoire and clonotypic phenotype and function. Dominant clonotypes are characterized by higher PD-1 expression and lower C127 expression compared to sub-dominant clonotypes and TCR avidity positively correlates with PD-1 expression. At low peptide concentrations, dominant clonotypes fail to survive in culture. In response to stimulation with peptides representing variant epitopes, sub-dominant clonotypes produce higher relative levels of cytokines and display greater capacity for cross-recognition compared to dominant clonotypes. These data indicate that dominant clonotypes within HIV-specific T cell responses display a phenotype consistent with ongoing exposure to cognate viral epitopes and suggest that cross-reactive, sub-dominant clonotypes may retain greater capacity to suppress replication of viral variants as well as to survive in the absence of strong antigenic signaling.

Antiretroviral Therapy Reduces the Magnitude and T Cell Receptor Repertoire Diversity of HIV-Specific T Cell Responses without Changing T Cell Clonotype Dominance

“…Clonotypic dominance within the repertoire was determined by sequencing and confirmed by colabeling tetramer-positive populations with anti-TRBV antibodies. As our group has shown previously (13,30,51), TCR repertoire data generated independently using these two methods correspond well, with a high degree of significance. Our data reported here showed a similarly high correspondence (Pearson r ϭ 0.85; P Ͻ 0.0001).…”

“…While the changes we observed in activation and memory phenotypes on CD8 ϩ T cells after initiation of ART have been reported previously for other cohorts, and while Yamamoto et al reported reductions in negative regulatory surface molecules on T cell populations (57), the measurement of phenotypic changes after initiation of ART on epitope-specific clonotypes has not been reported. Recent findings from our group established a relationship between dominance in the epitope-specific TCR repertoire and a PD-1 high CD127 low phenotype (13). By assessing epitopespecific clonotypic T cell populations before and after initiation of ART, we noted that dominant clonotypes had a PD-1 high phenotype compared to subdominant clonotypes, which had been established during chronic infection and which endured after initiation of ART.…”

“…Expression of PD-1 is closely related to antigen exposure and T cell exhaustion in several infection systems (10, 24, 43), and we have previously shown that PD-1 is expressed more highly on dominant clonotypes within epitopespecific T cell populations (13). Having demonstrated clonotypic remodeling after initiation of ART, we were interested in determining whether initiation of ART would influence the relationship between clonotypic dominance and PD-1 expression.…”

“…We recently demonstrated that within epitope-specific populations, individual clonotypes may differ markedly in their memory maturation phenotype but not in the expression of other markers, such as CD57, indicating a degree of senescence that is maintained across clonotypes (33). Our most recent work showed that dominant clonotypes express a PD-1 high CD127 low surface phenotype and recognize dominant circulating viral sequences, whereas subdominant clonotypes are better able to recognize and suppress epitope variants (13). Another study, by van Bockel et al, found that epitope-specific clonotypes are persistent over time in vivo and may contribute to the recognition and suppression of viral variants (54).…”

“…However, current methods for deep sequencing of TCR repertoires rely either on a very limited TRBV family primer set (55) or on multiplex PCR with a set of primers representing each TRBV family (45). These methods will need to be compared to the current state-of-the-art method, i.e., 5=-anchored PCR, which has been shown to be correlated highly with anti-TRBV antibody staining in defining epitope-specific TCR repertoires (13).…”