Dysregulated intrathymic development in the IL-2-deficient mouse leads to colitis-inducing thymocytes.
Gene-targeted mice lacking the IL-2 gene (IL-2 -/- mice) develop various forms of autoimmunity as well as severe colitis, either spontaneously in a conventional environment or after immunization with 2,4,6-trinitrophenol (TNP)-conjugated keyhole limpet hemocyanin (KLH) in a specific pathogen-free environment. We show here that the induction of colitis with TNP-KLH induces a change in the thymocyte population characterized by decreased numbers of double positive (DP; CD4+CD8+) thymocytes (IL-2 +/+, 45.2 x 10(6) vs IL-2 -/-, 23.6 x 10(6)) and increased numbers of single positive (SP; CD4+CD8- or CD4-CD8+) thymocytes (IL-2 +/+, 5.3 x 10(6) vs IL-2 -/-, 20.9 x 10(6)). The latter also bear activation markers. In addition, thymocytes from TNP-KLH-immunized IL-2 -/- mice produce more IFN-gamma and less IL-4 than similarly immunized IL-2 +/+ mice. These defects in thymocyte maturation and lymphokine production are IL-12 driven, since they are prevented when immunized IL-2 -/- mice are coadministered with anti-lL-12. Furthermore, we demonstrate that IL-2 -/- mice exhibit decreased cortical apoptosis as determined by thymocyte numbers and detection of apoptotic cells in situ. Finally, we show that colitis-inducing thymocytes are generated in the immunized IL-2 -/- thymus, since IL-2 +/+ mice develop colitis following injection of small numbers of single positive thymocytes from immunized IL-2 -/- mice but not from IL-2 +/+ mice. Taken together, these data indicate that, in the absence of IL-2, thymocyte maturation is abnormally directed by IL-12 toward the generation of mature, activated Th1-type thymocytes that are capable of mediating colitis.
Lúdvíksson
B R
BR
Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Gray
B
B
Strober
W
W
Ehrhardt
R O
RO
D000818:Animals; D000955:Antigens, T-Independent / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D003092:Colitis / Q000209:etiology* / Q000276:immunology* / Q000473:pathology; D006241:Haptens; D006433:Hemocyanins / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology; D007376:Interleukin-2 / Q000172:deficiency* / Q000235:genetics*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology*; D013950:Thymus Gland / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*
D000955:Antigens, T-Independent; D006241:Haptens; D007376:Interleukin-2; C054401:trinitrophenyl keyhole limpet hemocyanin; D018664:Interleukin-12; D006433:Hemocyanins