Antigens activated SOCS3+CD200R+CD4+ T cells are critical to Leishmania pathogenesis and a distinctive target for vaccine development

Abstract

The expression of suppression of cytokine signalling protein (SOCS3) has been posited as a critical determinant of T cells differentiation and maturation during visceral leishmaniasis (VL), however, the antigen-activated CD4+ T cell phenotypes expressing this protein have not been explored much. Since, the inherent nature of SOCS3 protein directs the polarization of CD4+ T cells towards anti-inflammatory Th2 axis, the identification of SOCS3 expressing T-cell phenotypes will provide a better understanding on Leishmania immunobiology. Our previous findings have delineated a distinct Leishmania antigens activated CD4+ T cells phenotype expressing CD200R receptor that acts as prime anti-inflammatory disease promoting subset. Here, in this study we observed that the SOCS3+ antigen activated CD200R+CD4+ T cells phenotype is succinctly involved in cytokines regulation during Leishmania infection. We further observed that CD200R+CD4+ T cells expressing higher levels of SOCS3 protein have the potential to polarize these cells to produce more IL-10, and less IL-12 & IFN-γ as compared to CD200R−CD4+T cells on exposure to whole killed Leishmania vaccine in a mice model of VL. Furthermore, the observed decline in splenic SOCS3 expression along with inflammatory factors like prostaglandin E2, upon abrogation of CD200R signalling in Leishmania infected animals suggest a coordinated role of CD200R and SOCS3 protein in VL pathogenesis. These findings prompted us to study the potential of CD200R and SOCS3 in the vaccine-induced immunity. Immunization with an in-house whole killed Leishmania vaccine adjuvanted with anti-CD200 antibodies not only reduced splenic SOCS3 expression but also enhanced CD4+ T cells' effector functions and their memory conversion. The down-regulation of splenic SOCS3 was also found correlated with reduced granuloma and parasitic load in SOCS3-low mice groups. Hence, the identified SOCS3+CD200R+CD4+ T cells subset reveals a potential disease-promoting phenotype that can be targeted to enhance the immunogenicity of Leishmania antigens. © 2025