ICOS and Bcl6-dependent pathways maintain a CD4 T cell population with memory-like properties during tuberculosis

• Published in: The Journal of experimental medicine Vol. 212; no. 5; pp. 715 - 728
• Main Authors: Moguche, Albanus O., Shafiani, Shahin, Clemons, Corey, Larson, Ryan P., Dinh, Crystal, Higdon, Lauren E., Cambier, C.J., Sissons, James R., Gallegos, Alena M., Fink, Pamela J., Urdahl, Kevin B.
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 04.05.2015
• Subjects: Animals; DNA-Binding Proteins - genetics; DNA-Binding Proteins - immunology; Gene Expression Regulation - immunology; Immunity, Cellular - genetics; Immunologic Memory; Inducible T-Cell Co-Stimulator Protein - genetics; Inducible T-Cell Co-Stimulator Protein - immunology; Lung - immunology; Lung - microbiology; Lung - pathology; Mice; Mice, Knockout; Mycobacterium tuberculosis; Mycobacterium tuberculosis - immunology; Proto-Oncogene Proteins c-bcl-6; Th1 Cells - immunology; Th1 Cells - pathology; Tuberculosis, Pulmonary - genetics; Tuberculosis, Pulmonary - immunology; Tuberculosis, Pulmonary - pathology
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20141518

Immune control of persistent infection with Mycobacterium tuberculosis (Mtb) requires a sustained pathogen-specific CD4 T cell response; however, the molecular pathways governing the generation and maintenance of Mtb protective CD4 T cells are poorly understood. Using MHCII tetramers, we show that Mtb-specific CD4 T cells are subject to ongoing antigenic stimulation. Despite this chronic stimulation, a subset of PD-1+ cells is maintained within the lung parenchyma during tuberculosis (TB). When transferred into uninfected animals, these cells persist, mount a robust recall response, and provide superior protection to Mtb rechallenge when compared to terminally differentiated Th1 cells that reside preferentially in the lung-associated vasculature. The PD-1+ cells share features with memory CD4 T cells in that their generation and maintenance requires intrinsic Bcl6 and intrinsic ICOS expression. Thus, the molecular pathways required to maintain Mtb-specific CD4 T cells during ongoing infection are similar to those that maintain memory CD4 T cells in scenarios of antigen deprivation. These results suggest that vaccination strategies targeting the ICOS and Bcl6 pathways in CD4 T cells may provide new avenues to prevent TB.