ThCTL expressing NKG2A/C/E represent a unique CD4 cytotoxic effector subset.

Abstract

Abstract Activated CD4 T cells differentiate into effector subsets tailored to fight widely diverse pathogens. CD4 T cell effectors can help antibody responses, secrete effector cytokines, and lyse infected cells. Cytotoxic CD4 T cells, termed ThCTL, synergize with antibody to provide strong protection against a lethal infection with influenza A virus (IAV) in mice and correlate with better disease outcome in humans. However, their regulation in vivo is not well studied. We find that IAV-generated ThCTL is localized to the lung, the site of viral replication, and express NKG2A/C/E, which is expressed only on a fraction of CD4 effectors. The expression of this marker does not impact cytotoxicity but may play a role in the infiltration or survival of the ThCTL. We used NKG2A/C/E to further characterize the ThCTL subset. We found that ThCTL can secrete effector cytokines, IFNg and TNFa and that they express markers consistent with high levels of activation and cytotoxicity. Microarray analysis indicates these ThCTL down-regulate markers for circulation: Ccr7, S1p1r, and Klf2, while up-regulating cytotoxic molecules: Prf1, Gzmc, and Gzmf. We find the generation of ThCTL in vivo is regulated by the context of late antigen and co-stimulation, such that ThCTL can be induced from effectors at day 6 post infection. Taken together, ThCTL consist of an activated subset of CD4 T cells with unique properties to combat IAV infection.