Ex Pluribus Unum: The CD4 T Cell Response against Influenza A Virus

Abstract

Current Influenza A virus (IAV) vaccines, which primarily aim to generate neutralizing antibodies against the major surface proteins of specific IAV strains predicted to circulate during the annual 'flu' season, are suboptimal and are characterized by relatively low annual vaccine efficacy. One approach to improve protection is for vaccines to also target the priming of virus-specific T cells that can protect against IAV even in the absence of preexisting neutralizing antibodies. CD4 T cells represent a particularly attractive target as they help to promote responses by other innate and adaptive lymphocyte populations and can also directly mediate potent effector functions. Studies in murine models of IAV infection have been instrumental in moving this goal forward. Here, we will review these findings, focusing on distinct subsets of CD4 T cell effectors that have been shown to impact outcomes. This body of work suggests that a major challenge for next-generation vaccines will be to prime a CD4 T cell population with the same spectrum of functional diversity generated by IAV infection. This goal is encapsulated well by the motto 'ex pluribus unum': that an optimal CD4 T cell response comprises many individual specialized subsets responding together.

Keywords: CD4 T cell; Th1; Th17; cytotoxic CD4 T cell; follicular helper cell; influenza virus; regulatory CD4 T cell.

Figure 1

Homotypic versus heterosubtypic immunity against IAV. The left-hand column depicts homotypic re-infection of an IAV-primed individual. In this case, neutralizing antibodies against the HA and NA of the challenge virus (or vaccine) preexist, which can prevent infection upon reencounter with a virus expressing the same HA and NA. The middle column depicts heterosubtypic re-infection, where prexisting antibodies raised by an initial IAV encounter cannot neutralize the newly encountered IAV, but T cells recognizing epitopes of viral proteins that are conserved between the priming and the challenge virus do preexist. In this case, viral infection is not prevented, resulting in infected cells presenting viral peptides on MHC-II. The final column indicates the major interactions through which antiviral CD4 T cells can contribute to heterosubtypic immunity after recognizing the viral antigens presented by MHC-II.

Figure 2

Many subsets of specialized CD4 T cells contribute to optimal protection against IAV. A schematic of the diverse types of CD4 T cell responses found to impact the outcomes of IAV infection in murine models. Key inflammatory factors induced by IAV infection known to guide the differentiation of subsets are shown in green, along with hallmark transcriptional regulators and secreted products of each subset. Dotted lines between subsets represent some of the possible plasticity reported in the literature between adjacent subsets.