MHC Class II Restricted Innate-Like Double Negative T Cells Contribute to Optimal Primary and Secondary Immunity to Leishmania major

Abstract

Although it is generally believed that CD4 ⁺ T cells play important roles in anti- Leishmania immunity, some studies suggest that they may be dispensable, and that MHC II-restricted CD3 ⁺CD4 ⁻CD8 ⁻ (double negative, DN) T cells may be more important in regulating primary anti- Leishmania immunity. In addition, while there are reports of increased numbers of DN T cells in Leishmania-infected patients, dogs and mice, concrete evidence implicating these cells in secondary anti- Leishmania immunity has not yet been documented. Here, we report that DN T cells extensively proliferate and produce effector cytokines (IFN-γ, TNF and IL-17) and granzyme B (GrzB) in the draining lymph nodes and spleens of mice following primary and secondary L. major infections. DN T cells from healed mice display functional characteristics of protective anti- Leishmania memory-like cells: rapid and extensive proliferation and effector cytokines production following L. major challenge in vitro and in vivo. DN T cells express predominantly (> 95%) alpha-beta T cell receptor (αβ TCR), are Leishmania-specific, restricted mostly by MHC class II molecules and display transcriptional profile of innate-like genes. Using in vivo depletion and adoptive transfer studies, we show that DN T cells contribute to optimal primary and secondary anti- Leishmania immunity in mice. These results directly identify DN T cells as important players in effective and protective primary and secondary anti- L. major immunity in experimental cutaneous leishmaniasis.

Author Summary

Although it is generally believed that CD4 ⁺ T cells mediate anti- Leishmania immunity, some studies suggest that CD3 ⁺CD4 ⁻CD8 ⁻ (double negative, DN) T cells may play a more important role in regulating primary anti- Leishmania immunity. Here, we report that DN T cells extensively proliferate and produce effector cytokines in mice following primary and secondary L. major infections. Leishmania-reactive DN T cells utilize αβ T cell receptor (TCR) and are restricted by MHC class II molecules. Strikingly, DN T cells from healed mice display functional characteristics of protective anti- Leishmania memory-like cells: rapid and extensive proliferation, effector cytokine production in vitro and in vivo, and accelerated parasite control following secondary L. major challenge. These results directly identify DN T cells as important players in protective primary and secondary anti- L. major immunity in experimental cutaneous leishmaniasis.