Interleukin-6 restricts pre-thymic T cell lineage commitment of progenitors driving loss of SIV control

Effective T cell reconstitution in people living with HIV is central to durable immune control and cure strategies. Sustained thymic output underpins T cell recovery and requires continuous seeding by T cell-committed progenitors originating in the bone marrow (BM). Using the SIV/rhesus macaque model, we identified a lymphoid thymus-seeding progenitor (TSP; CD4⁻CD8⁻CD34⁺CD38⁻CD7⁺) in BM that declined following SIV infection and closely associated with reduced T cell lineage biased differentiation of hematopoietic stem and progenitor cells (HSPCs). Importantly, both the decline in TSPs and the impairment of pre-thymic T cell potential were strongly associated with early loss of viral control, independent of peripheral T cell dynamics. Plasma interleukin-6 (IL-6) levels robustly predicted the magnitude of TSP loss and the restriction in T cell-biased HSPC differentiation. Transcriptomic and proteomic analyses revealed inflammatory imprinting of HSPCs characterized by activation of the IL-6-JAK-STAT axis, inflammasome engagement, and coordinated suppression of key T cell specification factors, including RUNX1, FYN, and ZAP70. In a nonanimal model of thymopoiesis, exposure of rhesus macaque or human HSPCs to IL-6 inhibited their transition from DN1 (CD38⁻) to DN2 (CD38⁺) TSP states, indicating an early block in T cell lineage commitment. Conversely, ex vivo blockade of IL-6 receptors restored thymocyte differentiation to levels comparable to that in untreated controls. Collectively, these findings demonstrate that pathogenic inflammation restricts pre-thymic T cell development early after infection, directly contributing to loss of viral control. These findings have important implications for understanding the mediators of anti-viral T cell immunity and HIV cure.