ABSTRACT
Tissue-resident memory T cells (TRM) provide optimal defense at the sites of infection, but signals regulating their development are unclear, especially for CD4 T cells. Here we identify two distinct pathways that lead to the generation of CD4 TRM in the lungs following influenza infection. The TRM are transcriptionally distinct from conventional memory CD4 T cells and share a gene signature with CD8 TRM. The CD4 TRM are superior cytokine producers compared with conventional memory cells, can protect otherwise naive mice against a lethal influenza challenge, and display functional specialization by inducing enhanced inflammatory responses from dendritic cells compared with conventional memory cells. Finally, we demonstrate than an interleukin (IL)-2-dependent and a novel IL-2-independent but IL-15-dependent pathway support the generation of cohorts of lung TRM.
Subject(s)
CD4-Positive T-Lymphocytes/physiology , CD8-Positive T-Lymphocytes/physiology , Dendritic Cells/immunology , Interleukin-15/metabolism , Lung/immunology , Orthomyxoviridae Infections/immunology , Orthomyxoviridae/immunology , Animals , Cell Differentiation , Cells, Cultured , Immunologic Memory , Inflammation Mediators/metabolism , Interleukin-15/genetics , Interleukin-2/metabolism , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Mice, Knockout , TranscriptomeABSTRACT
The mechanisms responsible for heterosubtypic immunity to influenza virus are not well understood but might hold the key for new vaccine strategies capable of providing lasting protection against both seasonal and pandemic strains. Memory CD4 T cells are capable of providing substantial protection against influenza both through direct effector mechanisms and indirectly through regulatory and helper functions. Here, we discuss the broad impact of memory CD4 T cells on heterosubtypic immunity against influenza and the prospects of translating findings from animal models into improved human influenza vaccines.
