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Title:   Author  item
                                            Stephensen, Charlesitem
                                            BOROWSKY, ALEXANDER - UCD PATHOLOGY LAB MEDitem
                                            LLOYD, KENT - UC DAVIS, COMPARATIVE MED
  Submitted to: Immunology
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 1/29/2007
                                    Publication  Date: 7/2/2007
                                    Citation: Stephensen, C.B., Borowsky, A.D., Lloyd, K.K. 2007. DISRUPTION OF RXRA GENE IN THYMOCYTES AND T LYMPHOCYTES MODESTLY ALTERS LYMPHOCYTE FREQUENCIES, PROLIFERATION, SURVIVAL AND T HELPER TYPE 1/TYPE 2 BALANCE. Immunology. 121:484-498.Interpretive Summary: Vitamin A and other related nutrients (e.g., vitamin D) regulate immune function and therefore affect the risk of developing infectious diseases, or chronic immune-mediated diseases, such as asthma or autoimmune diseases such as multiple sclerosis. In the present study we have examined how disruption of the gene for retinoid x receptor alpha (Rxra) interferes with the normal function of T lymphocytes, a key cell in mediating adaptive immune responses such as the response to immunization or infection. The Rxra gene mediates the activity of vitamin A, vitamin D and other nutrients on cellular function. We have found that disruption of Rxra modestly impairs the ability of these cells to proliferate normally, and alters their pattern of cytokine production. Both defects could impair the response of T lymphocytes to immunization or infection, and help explain how vitamin A deficiency disrupts immune function.
                                Technical Abstract: Retinoid X receptor (RXR) agonists, including the vitamin A metabolite 9-cis retinoic acid, decrease T lymphocyte apoptosis and promote Th2 development ex vivo. To examine the in vivo role of RXR-a in T lymphocyte development and function, we disrupted the Rxra gene in thymocytes and T lymphocytes using cyclizing recombinase (cre)-loxP-mediated excision of Rxra exon 4.  Cre expression was targeted to these cells using the Lck promoter.  Successful disruption of exon 4 was seen in thymocytes and T lymphocytes and a 58% reduction of RXR-a protein was seen in 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 percentages of T and B lymphocytes were also decreased in spleen and lymph nodes of knockout mice.  Ex vivo proliferation was decreased and apoptosis increased in T lymphocytes from knockout mice. Memory CD4+ T lymphocytes from knockout mice produced more IFN-g and 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 naïve CD4+ T lymphocytes, nor did Rxra disruption alter the serum IgG1/IgG2a response to immunization. In summary, disruption of Rxra altered T and B lymphocyte percentages, produced a modest Th1 bias in vivo, and altered T lymphocyte proliferation and apoptosis ex vivo.


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