A Molecular Signature for Il-10-Producing Th1 Cells in Protozoan Parasitic Diseases

Abstract

Control of the intracellular parasites causing malaria and visceral leishmaniasis (VL) is dependent on IFNγ+Tbet+CD4+ T (Th1) cells generated by infected hosts. IL-10 produced by Th1 cells mitigates subsequent inflammation and related pathology. However, IL-10-producing Th1 (Tr1) cells can also promote parasite persistence, as well as impair immunity following re-infection or vaccination. Here, we identify molecular and phenotypic signatures that distinguish Th1 cells from Tr1 cells in experimental VL caused by Leishmania donovani infection of C57BL/6 mice and in Plasmodium falciparum-infected humans participating in controlled human malaria infection (CHMI) studies. We identify LAG3 as an immune checkpoint target in VL, describe heterogeneity of co-inhibitory receptor expression by Tr1 cells and discovered a role for the transcription factor Pbx1 in suppressing CD4+ T cell cytokine production. Together, this work provides new insights into Tr1 cell functions that offer opportunities for strategies to modulate their functions to improve anti-parasitic immunity.