IL-21 signaling is essential for optimal host resistance against Mycobacterium tuberculosis infection.
IL-21 is produced predominantly by activated CD4+T cells and has pleiotropic effects on immunity via the IL-21 receptor (IL-21R), a member of the common gamma chain (γc) cytokine receptor family. We show that IL-21 signaling plays a crucial role in T cell responses during Mycobacterium tuberculosis infection by augmenting CD8+T cell priming, promoting T cell accumulation in the lungs, and enhancing T cell cytokine production. In the absence of IL-21 signaling, more CD4+and CD8+T cells in chronically infected mice express the T cell inhibitory molecules PD-1 and TIM-3. We correlate these immune alterations with increased susceptibility of IL-21R-/-mice, which have increased lung bacterial burden and earlier mortality compared to WT mice. Finally, to causally link the immune defects with host susceptibility, we use an adoptive transfer model to show that IL-21R-/-T cells transfer less protection than WT T cells. These results prove that IL-21 signaling has an intrinsic role in promoting the protective capacity of T cells. Thus, the net effect of IL-21 signaling is to enhance host resistance to M. tuberculosis. These data position IL-21 as a candidate biomarker of resistance to tuberculosis.
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts 01655, US.|Program in Immunology, Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts 02115, US.
Matthew G
MG
Booty
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts 01655, US.|Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.|ICVS/3B's, Portuguese Government Associate Laboratory, Braga/Guimarães, Portugal.
Palmira
P
Barreira-Silva
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts 01655, US.
Stephen M
SM
Carpenter
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts 01655, US.
Cláudio
C
Nunes-Alves
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts 01655, US.
Miye K
MK
Jacques
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts 01655, US.
Britni L
BL
Stowell
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts 01655, US.
Pushpa
P
Jayaraman
Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine, Tufts University, Grafton, MA 01536, US.
Gillian
G
Beamer
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts 01655, US.
Samuel M
SM
Behar
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000382:microbiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000382:microbiology; D016207:Cytokines / Q000378:metabolism; D060467:Disease Resistance / Q000276:immunology*; D005260:Female; D000072597:Hepatitis A Virus Cellular Receptor 2 / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D008168:Lung / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009169:Mycobacterium tuberculosis; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D015398:Signal Transduction; D014376:Tuberculosis / Q000276:immunology*; D000098546:Interleukin-21
D015415:Biomarkers; D016207:Cytokines; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D007378:Interleukins; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma; D000098546:Interleukin-21