CD4+NKG2D+ T cells in Crohn's disease mediate inflammatory and cytotoxic responses through MICA interactions.
OBJECTIVE
Crohn's disease (CD) is an inflammatory bowel disease characterized by uncontrolled immune responses to bacterial flora, with excessive activation of T lymphocytes. MICA is a stress-induced major histocompatibility complex-related molecule expressed on normal intestinal epithelial cells (IECs) and recognized by the NKG2D-activating receptor on CD8(+) T cells, gammadelta T cells, and natural killer cells. We examined the role of MICA-NKG2D interactions in the activation of T lymphocytes in CD.


METHODS
MICA expression was analyzed by flow cytometry on IECs isolated from patients with active inflammatory bowel disease and controls. NKG2D expression and function were analyzed on lamina propria and peripheral blood lymphocytes.


RESULTS
MICA expression was significantly increased on IECs in CD, with higher expression in macroscopically involved areas. A subset of CD4(+) T cells expressing NKG2D was increased in the lamina propria from patients with CD compared with controls and patients with ulcerative colitis. CD4(+)NKG2D(+) T cells with a Th1 cytokine profile and expressing perforin were increased in the periphery and in the mucosa in CD. CD4(+)NKG2D(+) T-cell clones were functionally active through MICA-NKG2D interactions, producing interferon-gamma and killing targets expressing MICA. IECs from patients with CD had the ability to expand this subset in vitro. CD4(+)NKG2D(+) lamina propria lymphocytes from patients with CD highly expressed interleukin-15R alpha, and interleukin-15 increased NKG2D and DAP10 expression in CD4(+)NKG2D(+) T-cell clones.


CONCLUSIONS
These findings highlight the role of MICA-NKG2D in the activation of a unique subset of CD4(+) T cells with inflammatory and cytotoxic properties in CD.
Allez
Matthieu
M
Service de Gastroentérologie, Hôpital Saint-Louis, Paris, France; INSERM Unité 662, Hôpital Saint-Louis, Paris, France. matthieu.allez@sls.aphp.fr
Tieng
Vannary
V
Nakazawa
Atsushi
A
Treton
Xavier
X
Pacault
Vincent
V
Dulphy
Nicolas
N
Caillat-Zucman
Sophie
S
Paul
Pascale
P
Gornet
Jean-Marc
JM
Douay
Corinne
C
Ravet
Sophie
S
Tamouza
Ryad
R
Charron
Dominique
D
Lémann
Marc
M
Mayer
Lloyd
L
Toubert
Antoine
A
D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002999:Clone Cells; D018920:Coculture Techniques; D003424:Crohn Disease / Q000097:blood / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D013505:Digestive System Surgical Procedures; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K; D010641:Phenotype; D011184:Postoperative Period; D011971:Receptors, Immunologic / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D018417:Th1 Cells / Q000378:metabolism
D016207:Cytokines; D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell