Protective CD4 T cells specific for M. tuberculosis (Mtb) are maintained in the lungs during active Mtb infection. Similar to memory CD4 T cells, persistence of these Mtb-specific cells requires intrinsic expression of Bcl6 and ICOS.

Chronic antigenic stimulation is known to cause T cell functional exhaustion and death. During Mtb infections, antigen specific CD4 T cells are subject to chronic antigenic stimulation but a sizeable population of these cells survives and maintains the ability to produce IFN-γ. How these cells are maintained is not yet understood. Mtb-specific CD4 T cells can be classified based on the surface expression of the inhibitory receptors PD1 and KLRG1. The PD1+ cells proliferate robustly but produce low amounts of IFN-γ while KLRG1+ cells proliferate less but produce large amounts of IFN-γ. Significantly, the PD1+ cells are capable of differentiating into KLRG1+ cells and not vice versa indicating that a self-renewing progenitor population may be contained within the PD1+ cells. On further characterization we have found that PD1+ cells are heterogeneous containing three different subsets based on expression of the chemokine receptor CXCR5 i.e. PD1+CXCR5hi cells that resemble Tfh cells, PD1+CXCR5int and PD1+CXCR5lo cells. We found that B cells were not required to maintain the Tfh like cells or overall Mtb-specific CD4 T cells. However, using mixed bone marrow chimeras we found that intrinsic CXCR5 expression on CD4 T cells is required to maintain Mtb-specific CD4 T cells. Taken together, these studies indicate that during Mtb infections, a subset of CD4 T cells capable of self-renewal is induced and intrinsic CXCR5 is important for its maintenance.

How Mycobacterium tuberculosis (Mtb) evades eradication from the lung despite an apparently robust Th1 response remains poorly understood. We addressed this question using MHCII tetramers to monitor Mtb-specific CD4 T cells in the mouse model. We found that the location, phenotype, and functional capacity of T cells specific for distinct Mtb epitopes differ, and depend upon the expression profile of the specific Mtb antigen recognized. Terminally differentiated Th1 cells (defined by their high expression of the transcription factor T-bet, the inhibitory receptor KLRG1, and an enhanced ability to produce IFN-γ) specific for Mtb ESAT-6, an antigen expressed throughout infection, were surprisingly found to reside in the lung-associated vasculature rather than the lung parenchyma. Those ESAT-6-specific effector T cells within the parenchyma had a reduced capacity to proliferate and produce IFN-γ. In contrast, T cells specific for Mtb Ag85B, an antigen with limited expression during chronic infection, were found to reside primarily within the lung parenchyma and to proliferate and produce IFN-γ robustly. Our results refute the long-held belief that Mtb persists despite an abundance of functional Mtb-specific Th1 cells within the lung, and suggest that only T cells that recognize Mtb antigens with limited expression during chronic infection retain their functional capacity. These findings have obvious implications for vaccine and immunotherapeutic approaches for tuberculosis.