Defining features of protective CD4 T cell responses to Mycobacterium tuberculosis

•Much is unclear about protective CD4 T cell responses against Mycobacterium tuberculosis.•Th1 responses are essential but other effector mechanisms also protect against Mtb.•Vaccines that generate fewer terminally differentiated T cells are more protective.•Mtb-specific CD4 T cells that rapidly enter the lung tissue are highly protective.

CD4 T cells are critical for control of Mycobacterium tuberculosis (Mtb) infection and represent the best hope for vaccine-elicited protection. However, little is understood about the properties of Mtb-specific CD4 T cells that mediate control, and the lack of correlates of protection present a significant barrier to the rational development of new vaccination and therapeutic strategies which are sorely needed. Here we discuss the features of protective CD4 T cells including recent evidence for IFN-γ dependent and independent mechanisms of protection, poor protection by terminally differentiated cells and the importance of T cell migratory capacity for the control of Mtb infection.