Thymic impairment and low IL-7 levels contribute to deficient immune recovery in relapsing visceral leishmaniasis.

Visceral leishmaniasis (VL) is a severe disease caused by Leishmania infantum in Brazil. Relapses have increased among immunocompetent patients; however, the underlying factors remain unclear. Previous studies have linked persistently low CD4+ T cell counts to VL relapses, suggesting that impaired immune reconstitution may favor recurrence. Here, we investigated whether immune activation and thymic output influence immune recovery in VL and shape the TCRVβ repertoire, predisposing patients to relapse. Patients with VL, followed for 12 months, were stratified according to relapse (R-VL,n = 5) or non-relapse (NR-VL,n = 10). Immune activation, senescence, and the TCRVβ repertoire were evaluated using flow cytometry, and thymic output was assessed through sjTREC quantification in CD4+ and CD8+ T cells. Plasma IL-7 levels were also measured. R-VL patients exhibited sustained immune activation, in contrast to the decline observed in NR-VL. Both groups showed high levels of immunosenescence throughout the follow-up period. All patients had low sjTREC levels during active VL; however, post-treatment levels were even lower in R-VL patients and were associated with reduced IL-7 levels. TCRVβ repertoire analysis showed differential mobilization between patients in the NR-VL and R-VL groups. Correlation analysis suggested that deficient thymic output may impair T cell replenishment, which is crucial for parasite control. Linear mixed-effects modeling showed that CD4+ T cell counts were influenced by synergistic effect between sjTREC and IL-7, as well were correlated with activation. In conclusion, our findings indicate that VL relapse is associated with sustained immune activation, reduced sjTREC levels (indicative of reduced thymic output), reduced IL-7 levels, and peripheral T cell disturbances. Together, these alterations may limit CD4+ T cell recovery and contribute to disease recurrence.