Interferon-gamma-expressing cells are a major source of interleukin-21 in inflammatory bowel diseases.
BACKGROUND
We previously demonstrated that in inflammatory bowel disease (IBD) there is enhanced production of interleukin (IL)-21, a cytokine that activates multiple pathways that sustain mucosal inflammation. However, the phenotype of IL-21-producing cells in IBD, and the cytokine(s) they coproduce, is not known. We here characterized the cell source of IL-21 and determined which factors regulate IL-21 in the human gut.


METHODS
Cytokines were analyzed in CD4+ T intestinal lamina propria lymphocytes (T-LPL) isolated from IBD patients and controls by flow cytometry. Moreover, IL-21 was evaluated in mucosal T follicular cells (TFH). To assess the involvement of IL-12 and IL-23 in the production of IL-21, T-LPL were activated in the presence or absence of IL-12 or IL-23.


RESULTS
The proportion of IL-21-producing CD4+ T-LPL was increased in IBD compared to controls. The majority of IL-21-producing T-LPL coexpressed interferon (IFN)-gamma, and to a lesser extent IL-4 or IL-17A. Activation of CD4+ T-LPL with IL-12 but not IL-23 enhanced the fraction of cells coexpressing IL-21 and IFN-gamma. TFH cells in LPL were identified by CXCR5 expression and expressed IL-21 both in IBD and controls; however, the fraction of IL-21-positive TFH cells was higher in Crohn's disease than in ulcerative colitis and controls. Treatment of CD4+ T-LPL with IL-12 enhanced the frequency of CXCR5+ IL-21-producing TFH cells.


CONCLUSIONS
These findings indicate that in IBD IL-21 is mostly produced by CD4+ T-LPL coexpressing IFN-gamma, reinforcing the concept that distinct subsets of T cells can produce IL-21.
Sarra
Massimiliano
M
Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy.
Monteleone
Ivan
I
Stolfi
Carmine
C
Fantini
Massimo Claudio
MC
Sileri
Pierpaolo
P
Sica
Giuseppe
G
Tersigni
Roberto
R
Macdonald
Thomas T
TT
Pallone
Francesco
F
Monteleone
Giovanni
G
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000032:analysis; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000276:immunology*; D018664:Interleukin-12 / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis; D053759:Interleukin-23 / Q000276:immunology; D015847:Interleukin-4 / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis* / Q000276:immunology*; D007413:Intestinal Mucosa / Q000737:chemistry / Q000276:immunology; D009092:Mucous Membrane / Q000276:immunology; D054380:Receptors, CXCR5 / Q000032:analysis; D000098546:Interleukin-21
C095085:CXCR5 protein, human; D016207:Cytokines; D020381:Interleukin-17; D053759:Interleukin-23; D007378:Interleukins; D054380:Receptors, CXCR5; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D000098546:Interleukin-21