Maintenance and function of antigen-specific CD4 T cells within the lung during tuberculosis
Moguche, Albanus O.
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Tuberculosis (TB) is a chronic pulmonary disease caused by the intracellular bacterium Mycobacterium tuberculosis (Mtb). Even though CD4 T cells are critical for containing Mtb, the immune system rarely eradicates the bacteria, necessitating the maintaining of an antigen-specific CD4 T cell response throughout the course of infection. How this response is maintained is not currently well understood. Here we show that in a murine model of TB, Mtb-specific CD4 T cells are subjected to chronic antigenic stimulation. Despite this chronic antigenic stimulation, a subset of these Mtb-specific CD4 T cells expressing the inhibitory receptor PD-1 exhibits hallmarks of memory T cells and their maintenance requires intrinsic expression of ICOS, the transcription factor Bcl6, and the chemokine receptor CXCR5. Furthermore we find that a majority of KLRG1+ IFN-γ producing CD4 T cells are located in the lung-associated vasculature and not in the lung parenchyma as previously thought. However, the PD-1+ population that shares features with follicular helper (Tfh) and memory T cells is principally located within the lung parenchyma. This distribution can be largely explained by considering the TB granuloma as a tertiary lymphoid structure that forms within the Mtb infected lung parenchyma. Contrary to previous reports, we found naïve CD44low CD4 T cells are excluded from lung parenchyma of uninfected mice but migrate into the lungs of Mtb-infected mice in a CCR7 dependent manner. PD-1+ Mtb-specific CD4 T cells express high levels of CD69 but have low levels of sphingosine-1-phosphate receptor 1 (S1PR1) and the transcription factor KLF2. In contrast, terminally differentiated KLRG1+ type 1 helper T cells (Th1) cells exhibit elevated expression of S1PR1 and KLF2, but are CD69low. These expression profiles likely explain the differential localization of these Mtb-specific cell populations and suggest that when effector Th1 cells are generated within the granuloma or draining lymph nodes, they egress into the blood in an S1P1R mediated manner. Our results help explain why the frequency of Th1 cells circulating in the blood does not correlate with immune protection, and provides a framework for understanding how immunity against TB is shaped by CD4 T cell trafficking into and out of granulomas. Finally, we found that CD4 T cells recognizing Mtb antigens expressed throughout infection have a reduced capacity to produce protective cytokines and are restricted in their ability to control Mtb due to persistent stimulation by antigen. Conversely, CD4 T cells that recognize different Mtb antigens whose expression wanes with chronic infection have a limited capacity to mediate protection because of suboptimal stimulation by cognate antigen. Collectively, these studies expand our understanding of the mechanisms that promote the maintenance and function of antigen-specific CD4 T cells in the lung during TB. The insights gained should aid in the rational design of new vaccines, not only against TB, but also against other chronic disease conditions in which maintenance of antigen specific CD4 T cells is paramount.
- Immunology