LAG-3- and CXCR5-expressing CD4 T cells display progenitor-like properties during chronic visceral leishmaniasis

Maintenance of CD4 T cells during chronic infections is vital for limiting pathogen burden and disease recrudescence. Although inhibitory receptor expression by CD4 T cells is commonly associated with immune suppression and exhaustion, such cell-intrinsic mechanisms that control activation are also associated with cell survival. Using a mouse model of visceral leishmaniasis (VL), we discovered a subset of lymphocyte activation gene 3 (LAG-3)-expressing CD4 T cells that co-express CXCR5. Although LAG3⁺CXCR5⁺ CD4 T cells are present in naive mice, they expand during VL. These cells express gene signatures associated with self-renewal capacity, suggesting progenitor-like properties. When transferred into Rag1^-/- mice, these LAG3⁺CXCR5⁺ CD4 T cells differentiated into multiple effector types upon Leishmania donovani infection. The transcriptional repressor B cell lymphoma-6 was partially required for their maintenance. Altogether, we propose that the LAG3⁺CXCR5⁺ CD4 T cell subset could play a role in maintaining CD4 T cell responses during persistent infections.