T-Cell Receptor (TCR) Clonotype-Specific Differences in Inhibitory Activity of HIV-1 Cytotoxic T-Cell Clones Is Not Mediated by TCR Alone

Abstract

Functional analysis of T-cell responses in HIV-infected individuals has indicated that virus-specific CD8 ϩ T cells with superior antiviral efficacy are well represented in HIV-1 controllers but are rare or absent in HIV-1 progressors. To define the role of individual T-cell receptor (TCR) clonotypes in differential antiviral CD8 ϩ T-cell function, we performed detailed functional and mass cytometric cluster analysis of multiple CD8 ϩ T-cell clones recognizing the identical HLA-B*2705-restricted HIV-1 epitope KK10 (KRWIILGLNK). Effective and ineffective CD8 ϩ T-cell clones segregated based on responses to HIV-1-infected and peptide-loaded target cells. Following cognate peptide stimulation, effective HIV-specific clones displayed significantly more rapid TCR signal propagation, more efficient initial lytic granule release, and more sustained nonlytic cytokine and chemokine secretion than ineffective clones. To evaluate the TCR clonotype contribution to CD8 ϩ T-cell function, we cloned the TCR ␣ and ␤ chain genes from one effective and two ineffective CD8 ϩ T-cell clones from an elite controller into TCR-expressing lentivectors. We show that Jurkat/MA cells and primary CD8 ϩ T cells transduced with lentivirus expressing TCR from one of the ineffective clones exhibited a level of activation by cognate peptide and inhibition of in vitro HIV-1 infection, respectively, that were comparable to those of the effective clonotype. Taken together, these data suggest that the potent antiviral capacity of some HIV-specific CD8 ϩ T cells is a consequence of factors in addition to TCR sequence that modulate functionality and contribute to the increased antiviral capacity of HIV-specific CD8 ϩ T cells in elite controllers to inhibit HIV infection.

T cell receptors for the HIV KK10 epitope from patients with differential immunologic control are functionally indistinguishable

“…Therefore, our results suggest that differences in CTL responses in HCs and CPs were not due to differences in functional properties of their TCRs. While our results extend considerably the studies recently reported by Flerin et al (27), they contrast with previous data showing divergent function in CTL clones from one HC (CTR203) and two CPs (CR338 and FEN33), from which TCRs HC25, CP27, and CP7.9 tested here were derived (8). Unfortunately, the original CTL clones are no longer viable, preventing their direct comparison with transduced T cells in our assays.…”

“…Thus, there is evidence to suggest that immunologic control of HIV may be a function of the TCRs that mediate HIV-specific immunity (26). A recent report based on data from a single HC indicated that clonotypespecific differences between CTLs are not dependent on their TCRs alone (27). However, those results do not address the role of TCRs in HIV control because they did not compare TCRs from HCs and CPs.…”

CD4 + T cell–mediated HLA class II cross-restriction in HIV controllers

“…We show here that TCR affinity is also a key determinant of CD4 + T cell cytotoxic function, which has major implications for understanding the basis of HIV control. Recent findings suggest that cellular factors independent of TCR affinity may also contribute to the efficient cytolytic capacity of HIV controller CD8 + T cells (29). A limitation of our study is that we did not assess TCR-independent factors, such as the expression of costimulatory receptors.…”

CD8+ T cells in HIV control, cure and prevention

“…HLA alleles associated with HIV control impart thymic selection for TCR repertoires with increased HIV recognition and variant cross-reactivity 65 . Although differential TCR usage alone is insufficient to explain spontaneous control or confer functional differences in CD8 + T cells [66][67][68] , cross-reactive TCRs have been shown to limit viral escape pathways in controllers, consistent with the findings that mutations within epitopes targeted predominantly by controllers are poorly tolerated due to impaired viral replication 69,70 and that their recognition is maintained in controllers by cross-reactive TCRs and de novo responses [71][72][73] .…”