Distinct functions of antigen-specific CD4 T cells during murine Mycobacterium tuberculosis infection.
The immune response elicited after Mycobacterium tuberculosis (Mtb) infection is critically dependent on CD4 T cells during both acute and chronic infection. How CD4 T-cell responses are maintained throughout infection is not well understood, and evidence from other infection models has suggested that, under conditions of chronic antigen stimulation, T cells can undergo replicative exhaustion. These findings led us to determine whether subpopulations of CD4 T cells existed that displayed markers of terminal differentiation or exhaustion during murine Mtb infection. Analysis of antigen-specific effector CD4 T cells revealed that programmed death-1 (PD-1) and the killer cell lectin-like receptor G1 (KLRG1) delineated subpopulations of T cells. PD-1-expressing CD4 T cells were highly proliferative, whereas KLRG1 cells exhibited a short lifespan and secreted the cytokines IFNγ and TNFα. Adoptive transfer studies demonstrated that proliferating PD-1-positive CD4 T cells differentiated into cytokine-secreting KLRG1-positive T cells, but not vice versa. Thus, proliferating PD-1-positive cells are not exhausted, but appear to be central to maintaining antigen-specific effector T cells during chronic Mtb infection. Our findings suggest that antigen-specific T-cell responses are maintained during chronic mycobacterial infection through the continual production of terminal effector cells from a proliferating precursor population.
Reiley
William W
WW
Trudeau Institute, Saranac Lake, NY 12983, USA.
Shafiani
Shahin
S
Wittmer
Susan T
ST
Tucker-Heard
Glady's
G
Moon
James J
JJ
Jenkins
Marc K
MK
Urdahl
Kevin B
KB
Winslow
Gary M
GM
Woodland
David L
DL
D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D037181:Lectins, C-Type; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology*
D000942:Antigens, Bacterial; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; C451496:Klrg1 protein, mouse; D037181:Lectins, C-Type; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic