Reprogrammation des LT CD8 spécifiques du VIH-1 : vers une perspective de rémission de l'infection

CD8+ T cells play a pivotal role in the control of viral infections and cancer by eliminating infected or damaged cells through cytotoxic activity and cytokine production. However, persistent antigen exposure promotes the upregulation of inhibitory checkpoint molecules, the acquisition of exhaustion features, and functional decline. In addition, the capacity of antigen-specific CD8+ T cells can be impaired by intrinsic defects that extend beyond the exhaustion program. Such dysfunctional state compromises the ability of CD8+ T cells to sustain durable responses and represents a major barrier to immune control in persistent infections. A paradigmatic example is HIV-1 infection. A potent HIV-specific CD8+ T cell response is mobilized during acute infection leading to a marked decline in viremia. However, these cells display functional impairments, such as limited cytotoxicity and inefficient trafficking, that undermine their capacity to fully control infection. During chronic infection, the progressive reinforcement of the exhaustion program further diminishes their proliferative and antiviral capacities. CD8 T-cell fate in chronic infection is largely modulated and controlled by the presence of transcription factors. ID2 protein was described as a transcriptional regulator regulating and promoting terminal differentiation of CD8+ T-cells. Nevertheless, we recently found its gene expression enriched in the molecular program of HIV-1-specific CM CD8+ T-cells from HICs when compared with non-controllers. We hypothesise that ID2 expression is of importance for the acquisition of an optimal HIV-1-specific memory CD8+ T-cell response, and its expression could there embody a marker of quality in chronic infection. To address this assumption, two main objectives were established during my thesis: (i) characterising ID2 protein expression in human CD8+ T-cells as we lack understanding about ID2 protein expression in human memory CD8 T cells, and (ii) studying ID2 expression in models of HIV and SIV control, particularly in the scope of antigen-specific memory CD8+ T-cells. I found that ID2 expression in memory CD8+ T-cells was associated to a subset endowed with high proliferative capacities, retained expression of memory and survival markers and robust production of (IFN)-γ and TNF-α despite weak mobilisation of the mTORC1 pathway. I further identify a population co-expressing ID2 and the stemness marker TCF1 which exhibited strong memory potential while simultaneously displaying broad effector activity. Upon activation, these cells restrained upregulation of activation and exhaustion markers while retaining IL7R expression. TCF1+ID2+ memory CD8+ T cells showed superior capacity to expand and respond upon repeated antigen stimulation, and they constituted the large majority of the responsive virus-specific memory CD8+ T cell compartment in the context of naturally controlled CMV, HIV-1, and SIVmac251 infections. These findings suggest that virus-specific CD8+ T cells simultaneously expressing TCF1 and ID2 represent a poised memory state capable of sustaining calibrated antiviral pressure and are particularly suited to the control of persistent infections.