Harnessing CD4⁺ T cell responses in HIV vaccine development

Abstract

CD4(+) T cells can perform a panoply of tasks to shape an effective response against a pathogen. Limited attention has been paid to the potential importance of functional CD4(+) T cell responses in the context of the development of next-generation vaccines, including HIV vaccines. Many CD4(+) T cell functions are newly appreciated and only partially understood. A workshop was held as a forum to bring together a small group of experts to exchange ideas on the role of CD4(+) T cells in developing durable functional antibody responses, via follicular helper T cells, as well as on the roles of CD4(+) T cells in other aspects of protective immunity. Here we discuss whether CD4(+) T cell responses may represent a beneficial component of an efficacious HIV vaccine.

Figure 1

CD4⁺ T cell functions in protection against HIV. (a) T_FH cells are defined by their localization in the B cell follicles and expression of the transcription factor BCL6. T_FH cells have an essential role in the initiation and maintenance of germinal centers (GCs), the lymphoid tissue sites of B cell proliferation and affinity maturation for the development of high-affinity antibodies. T_FH cells select the best germinal center B cells by providing necessary signals for B cell survival, proliferation and differentiation. Moreover, T_FH cells are crucial in inducing high levels of somatic hypermutations, which are a common feature of broadly neutralizing antibodies against HIV. (b) T_H1 CD4⁺ T cells can directly recognize infected cells through viral peptides bound to HLA class II and can respond with secretion of the cytokines IFN-γ and tumor necrosis factor-α (TNF-α). CD4⁺ T cells can also directly kill HIV-infected cells, probably through perforin and granzyme A/B secretion. Eomesodermin (Eomes) is a transcription factor associated with cytolytic CD4⁺ T cells. T-bet is required for T_H1 cells. (c) CD4⁺ T cells are essential for the maintenance of mucosal integrity and control of gastrointestinal microflora, through IL-17–mediated attraction of neutrophils and IL-22–mediated repair of epithelial cells. CD4⁺ T cells can also attract CD8⁺ T cells via IFN-γ–dependent mechanisms and aid their tissue migration.