Disruption of Rxra gene in thymocytes and T lymphocytes modestly alters lymphocyte frequencies, proliferation, survival and T helper type 1/type 2 balance.
Retinoid X receptor (RXR) agonists, including the vitamin A metabolite 9-cis retinoic acid, decrease T-lymphocyte apoptosis and promote T helper type 2 (Th2) development ex vivo. To examine the in vivo role of RXR-alpha in T-lymphocyte development and function, we disrupted the Rxra gene in thymocytes and T lymphocytes using cyclization recombinase (Cre)-loxP-mediated excision of Rxra exon 4. Expression of Cre was targeted to these cells using the Lck promoter. Successful disruption of exon 4 was seen in thymus and T lymphocytes. Mice were healthy and the thymus, spleen and lymph nodes appeared normal. However, knockout mice had a lower percentage of double-positive (CD4(+) CD8(+)) and a higher percentage of double-negative thymocytes than wild-type mice. The percentage of splenic B lymphocytes was lower in unimmunized and ovalbumin-immunized knockout mice and the percentage of T lymphocytes was lower in immunized knockout mice. Ex vivo proliferation was decreased and apoptosis was increased in T lymphocytes from knockout mice. Memory CD4(+) T lymphocytes from knockout mice produced more interferon-gamma and interleukin-2 (IL-2) and less IL-5 and IL-10 than memory cells from wild-type mice, indicating a Th1 bias in vivo. However, Rxra disruption did not similarly bias ex vivo differentiation of naive CD4(+) T lymphocytes, nor did Rxra disruption alter the serum immunoglobulin G1/immunoglobulin G2a response to immunization. In summary, disruption of Rxra altered the percentages of T and B lymphocytes, produced a Th1 bias in vivo, and altered T-lymphocyte proliferation and apoptosis ex vivo. These differences were modest in magnitude and their impact on disease resistance is yet to be examined.
Stephensen
Charles B
CB
USDA Western Human Nutrition Research Center and Nutrition Department, University of California, Davis, CA 95616, USA. cstephen@whnrc.usda.gov
Borowsky
Alexander D
AD
Lloyd
Kevin C Kent
KC
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D007114:Immunization; D007156:Immunologic Memory; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047490:Retinoid X Receptor alpha / Q000235:genetics* / Q000378:metabolism; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology*; D014407:Tumor Cells, Cultured
D016207:Cytokines; D047490:Retinoid X Receptor alpha