Circulating and gut-resident human Th17 cells express CD161 and promote intestinal inflammation.
The C-type lectin-like receptor CD161, which has recently been described to promote T cell expansion, is expressed on a discrete subset of human CD4 T cells. The function of such cells, however, has remained elusive. We now demonstrate that CD161(+) CD4 T cells comprise a circulating and gut-resident T helper 17 (Th17) cell population. During Crohn's disease (CD), these CD161(+) cells display an activated Th17 phenotype, as indicated by increased expression of interleukin (IL)-17, IL-22, and IL-23 receptor. CD161(+) CD4 T cells from CD patients readily produce IL-17 and interferon gamma upon stimulation with IL-23, whereas, in healthy subjects, priming by additional inflammatory stimuli such as IL-1beta was required to enable IL-23-induced cytokine release. Circulating CD161(+) Th17 cells are imprinted for gut homing, as indicated by high levels of CC chemokine receptor 6 and integrin beta7 expression. Supporting their colitogenic phenotype, CD161(+) Th17 cells were found in increased numbers in the inflammatory infiltrate of CD lesions and induced expression of inflammatory mediators by intestinal cells. Our data identify CD161(+) CD4 T cells as a resting Th17 pool that can be activated by IL-23 and mediate destructive tissue inflammation.
Kleinschek
Melanie A
MA
Department of Immunology, Schering-Plough Biopharma, Palo Alto, CA 94304, USA. melanie.kleinschek@spcorp.com
Boniface
Katia
K
Sadekova
Svetlana
S
Grein
Jeff
J
Murphy
Erin E
EE
Turner
Scott P
SP
Raskin
Lisa
L
Desai
Bela
B
Faubion
William A
WA
de Waal Malefyt
Rene
R
Pierce
Robert H
RH
McClanahan
Terrill
T
Kastelein
Robert A
RA
D002465:Cell Movement; D003424:Crohn Disease / Q000276:immunology / Q000473:pathology; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D007249:Inflammation / Q000276:immunology* / Q000473:pathology*; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D053759:Interleukin-23 / Q000276:immunology; D007422:Intestines / Q000276:immunology* / Q000473:pathology*; D008213:Lymphocyte Activation; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000276:immunology*; D009928:Organ Specificity; D010641:Phenotype; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000473:pathology*
D020381:Interleukin-17; D053759:Interleukin-23; C527203:KLRB1 protein, human; D055651:NK Cell Lectin-Like Receptor Subfamily B; D007371:Interferon-gamma