Background
Depletion studies in non-human primates demonstrated the crucial role of CD8 T cells in controlling SIV replication. However, the precise mechanisms underlying the control of HIV replication remain elusive. Lymph nodes (LN) are a primary site of HIV replication, and studying the CD8 T cell response at this level may provide additional insights.
Methods
We performed an in-depth characterization of HIV-specific CD8 T cells of matched blood and LN samples from 5 chronic HIV infected individuals (CHI) and 4 HIV controllers by scRNA-seq and scTCR-Seq. In addition, longitudinal blood samples collected from 3 HIV controllers were also evaluated over-time (median interval years=11).
Results
A total of 63’881 and 32’922 HIV-specific CD8 T cells were sequenced from blood and LN, respectively. Consistently with previous studies, HIV-specific CD8 T cells showing canonical cytotoxic functions (granzyme B, perforin) were rare ex vivo in LN of both CHI and controllers. However, blood and, to a greater extent, LN HIV-specific CD8 T cells of controllers were enriched (p<2-16) in cells characterized by stemness markers (i.e. TCF7, IL7R, BACH2). This population, representing up to 63% of HIV-specific CD8 T cells in controllers, expressed the receptor GPR183 (EBI2), responsible for cell positioning at the T:B border in LN, and the effector molecule granzyme K. Interestingly, follicular-homing CXCR5+ HIV specific CD8 T cells in LN of controllers were also enriched in stem-like markers such as IL7R and CCR7 (p<10-18), while LN CXCR5+ HIV specific CD8 T cells of CHI expressed more exhaustion markers (TIGIT, CD160, p<10-5). Finally, TCR repertoire analysis revealed that HIV-specific CD8 T cells of CHI were more oligoclonal (blood, p=0.03; LN, p=0.25), suggesting the selection and/or elimination of some clonotypes during chronic infection. Of note, longitudinal analyses revealed that the clonotypic distribution of HIV-specific T cells may evolve in controllers, with expansion of subdominant clonotypes associated with transcriptomic traces of recent TCR engagement.
Conclusions
This study suggests that LN HIV-specific CD8 T cells in controllers harbor a distinct “stem-like” transcriptomic profile, possibly underlying an enhanced proliferative potential, associated with an optimal positioning in the LN microenvironment. Interestingly, both the transcriptomic profile and the TCR repertoire of HIV-specific CD8 T cells of HIV controllers can evolve with time, suggesting a dynamic adaptation of the immune response.
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