ICOS and Bcl6-dependent pathways maintain a CD4 T cell population with memory-like properties during tuberculosis.
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.
Seattle Biomedical Research Institute (renamed Center for Infectious Disease Research), Seattle, WA 98109 Department of Immunology, University of Washington School of Medicine, Seattle, WA 98104.
Albanus O
AO
Moguche
Seattle Biomedical Research Institute (renamed Center for Infectious Disease Research), Seattle, WA 98109.
Shahin
S
Shafiani
Seattle Biomedical Research Institute (renamed Center for Infectious Disease Research), Seattle, WA 98109 Department of Immunology, University of Washington School of Medicine, Seattle, WA 98104.
Corey
C
Clemons
Seattle Biomedical Research Institute (renamed Center for Infectious Disease Research), Seattle, WA 98109 Department of Immunology, University of Washington School of Medicine, Seattle, WA 98104.
Ryan P
RP
Larson
Seattle Biomedical Research Institute (renamed Center for Infectious Disease Research), Seattle, WA 98109.
Crystal
C
Dinh
Department of Immunology, University of Washington School of Medicine, Seattle, WA 98104.
Lauren E
LE
Higdon
Department of Immunology, University of Washington School of Medicine, Seattle, WA 98104.
C J
CJ
Cambier
Seattle Biomedical Research Institute (renamed Center for Infectious Disease Research), Seattle, WA 98109.
James R
JR
Sissons
Department of Immunology, International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, India.
Alena M
AM
Gallegos
Department of Immunology, University of Washington School of Medicine, Seattle, WA 98104.
Pamela J
PJ
Fink
Seattle Biomedical Research Institute (renamed Center for Infectious Disease Research), Seattle, WA 98109 Department of Immunology, University of Washington School of Medicine, Seattle, WA 98104 kevin.urdahl@cidresearch.org.
Kevin B
KB
Urdahl
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D007111:Immunity, Cellular / Q000235:genetics; D007156:Immunologic Memory; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D051560:Proto-Oncogene Proteins c-bcl-6; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology; D014397:Tuberculosis, Pulmonary / Q000235:genetics / Q000276:immunology* / Q000473:pathology
C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D051560:Proto-Oncogene Proteins c-bcl-6