Many infectious diseases are associated with potent inflammatory responses. These are required to control infection, but can also damage tissue and cause disease if not appropriately regulated. IL-10 has emerged as an important immune regulator that protects tissues by dampening inflammation. Under conditions of chronic infection, pro-inflammatory CD4⁺ T cells initiate IL-10 production as a mechanism of self-regulation. We recently identified IL-10 production by IFNγ-producing, T-bet⁺ CD4⁺ T (Th1) cells as a critical immunoregulatory mechanism during malaria caused by Plasmodium falciparum and visceral leishmaniasis (VL) caused by Leishmania donovani. We found that IL-10-producing Th1 (type 1 regulatory; Tr1) cells potently suppressed anti-parasitic immunity and promoted persistent infection. However, IL-10 produced by these same cells also prevented tissue damage caused by the pro-inflammatory cytokines TNF and IFNγ. We have now generated novel data sets from human and mouse CD4⁺ T cell subsets isolated during malaria and VL that allowed us to identify molecular signatures for Tr1 cells, as well as dysfunctional CD4⁺ T cells present in sites of infection and active disease. We used this data to identify novel immune checkpoint molecules that may be safely targeted for clinical advantage, including improving vaccine efficacy and drug treatment against infectious diseases.