Classical CD4 T cells as the cornerstone of antimycobacterial immunity

Tuberculosis is a significant health problem without an effective vaccine to combat it. A thorough understanding of the immune response and correlates of protection is needed to develop a more efficient vaccine. The immune response against Mycobacterium tuberculosis (Mtb) is complex and involves all aspects of the immune system, however, the optimal protective, non‐pathogenic T cell response against Mtb is still elusive. This review will focus on discussing CD4 T cell immunity against mycobacteria and its importance in Mtb infection with a primary focus on human studies. We will in particular discuss the large heterogeneity of immune cell subsets that have been revealed by recent immunological investigations at an unprecedented level of detail. These studies have identified specific classical CD4 T cell subsets important for immune responses against Mtb in various states of infection. We further discuss the functional attributes that have been linked to the various subsets such as upregulation of activation markers and cytokine production. Another important topic to be considered is the antigenic targets of Mtb‐specific immune responses, and how antigen reactivity is influenced by both disease state and environmental exposure(s). These are key points for both vaccines and immune diagnostics development. Ultimately, these factors are holistically considered in the definition and investigations of what are the correlates on protection and resolution of disease.