A subset of CD4+ effector memory T cells limit immunity to pulmonary viral infection and prevent tissue pathology via activation of latent TGFβ

Abstract

AbstractA rapid immune response to pathogen re-exposure underpins immunological memory, with protection against divergent pathogens such as heterologous or novel viral strains requiring cross­reactive memory T cells. Understanding the pathways that control memory T cell function is therefore important for the rational design of viral vaccines and will aid the discovery of therapies to boost anti-viral immunity. Here, we identify a sub-population of memory T cells that limit secondary immune responses to viral re-infection, which is crucial in preventing host tissue damage. We show that a population of CD4+effector memory T (TEM) cells activate the important immunoregulatory cytokine TGFβ, via expression of an integrin, αvβ8. Integrin αvβ8 expression marks a transcriptionally distinct sub-population of CD4+TEM, enriched for anti-inflammatory pathways. Loss of integrin αvβ8 on murine CD4+TEM, but not Foxp3+regulatory T cells (TREG), led to exacerbated virus-specific CD8+T cell responses following secondary influenza A virus (IAV) infection, which was associated with enhanced viral clearance. However, although accelerating clearance, loss of integrin αvβ8 expression on CD4+TEMresulted in enhanced lung pathology following secondary IAV infection, which was completely reversed by adoptive transfer of αvβ8+CD4+TEMcells. These data highlight a new pathway by which a distinct CD4+memory T cell subset restrains anti-viral immunity to prevent host tissue damage during secondary viral infection. Such pathways could be targeted therapeutically to either boost memory T-cell-mediated immunity or restrain host tissue damage during viral infection.