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

Abstract

Maintenance of CD4 Tcells during chronic infections is vital for limiting pathogen burden and disease recrudescence. Although inhibitory receptor expression by CD4 Tcells 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 Tcells that co-express CXCR5. Although LAG3+CXCR5+ CD4 Tcells 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 Tcells 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 Tcell subset could play a role in maintaining CD4 Tcell responses during persistent infections.