Fidelity of pathogen-specific CD4+ T cells to the Th1 lineage is controlled by exogenous cytokines, interferon-gamma expression, and pathogen lifestyle.
The degree of lineage stability achieved by pathogen-specific CD4(+) T cells in vivo, and how this impacts host defense against infection, remains unclear. We demonstrate that in response to Th1-polarizing intracellular bacterial or viral pathogens, only 80%-90% of responding polyclonal T cells become indelibly committed to this lineage. Th1 commitment was nearly invariant in cells that proliferated extensively, but perturbations to the extrinsic cytokine milieu or the pathogen's ability to enter the cytosol impeded commitment and promoted plasticity for future IL-17 expression. Conversely, cell-intrinsic interferon-gamma expression and acquisition of permissive chromatin at the Ifng gene during priming predicted heritable Th1 commitment. Importantly, CD4(+) T cells that retained plasticity conferred protection against Mycobacterium tuberculosis, while these protective effects were abolished with Th17 polarization. These findings illustrate the immune signals that induce memory CD4(+) T cell responses required for maintaining host defense against infection yet are adaptable in novel environmental contexts.
Curtis
Meredith M
MM
Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195, USA.
Rowell
Emily
E
Shafiani
Shahin
S
Negash
Amina
A
Urdahl
Kevin B
KB
Wilson
Christopher B
CB
Way
Sing Sing
SS
D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019070:Cell Lineage / Q000276:immunology; D016207:Cytokines / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D018664:Interleukin-12 / Q000276:immunology; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009169:Mycobacterium tuberculosis / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology
D016207:Cytokines; D018664:Interleukin-12; D007371:Interferon-gamma