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

TitleICOS and Bcl6-dependent pathways maintain a CD4 T cell population with memory-like properties during tuberculosis.
Publication TypeJournal Article
Year of Publication2015
AuthorsMoguche AO, Shafiani S, Clemons C, Larson RP, Dinh C, Higdon LE, Cambier CJ, Sissons JR, Gallegos AM, Fink PJ, Urdahl KB
JournalJ Exp Med
Volume212
Issue5
Pagination715-28
Date Published2015 May 04
ISSN1540-9538
KeywordsAnimals, DNA-Binding Proteins, Gene Expression Regulation, Immunity, Cellular, Immunologic Memory, Inducible T-Cell Co-Stimulator Protein, Lung, Mice, Mice, Knockout, Mycobacterium tuberculosis, Proto-Oncogene Proteins c-bcl-6, Th1 Cells, Tuberculosis, Pulmonary
Abstract

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.

DOI10.1084/jem.20141518
Alternate JournalJ. Exp. Med.
PubMed ID25918344
PubMed Central IDPMC4419347
Grant ListR21 AI097950 / AI / NIAID NIH HHS / United States
T21-CA009537 / CA / NCI NIH HHS / United States
T32 CA009537 / CA / NCI NIH HHS / United States
R01 AI076327 / AI / NIAID NIH HHS / United States
R01 AI064318 / AI / NIAID NIH HHS / United States
U19 AI106761 / AI / NIAID NIH HHS / United States