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The Balance Between CD45RC^high and CD45RC^low CD4 T Cells in Rats Is Intrinsic to Bone Marrow-Derived Cells and Is Genetically Controlled¹

Jean-Francois Subra^2,*, Bastien Cautain^2,*, Emmanuel Xystrakis^*, Magali Mas^*, Dominique Lagrange^*, Harry van der Heijden, Marie-Jose van de Gaar, Philippe Druet^*, Gilbert J. Fournié^*, Abdelhadi Saoudi^3,* and Jan Damoiseaux

^* Institut National de la Santé et de la Recherche Médicale, Unité 28, Institut Fédératif de Recherche 30, Hôpital Purpan and Université Paul Sabatier, Toulouse, France; and Department of Immunology, University Maastricht, Maastricht, The Netherlands

The level of CD45RC expression differentiates rat CD4 T cells in two subpopulations, CD45RC^high and CD45RC^low, that have different cytokine profiles and functions. Interestingly, Lewis (LEW) and Brown Norway (BN) rats, two strains that differ in their ability to mount type 1 and type 2 immune responses and in their susceptibility to autoimmune diseases, exhibit distinct CD45RC^high/CD45RC^low CD4 T cell ratios. The CD45RC^high subpopulation predominates in LEW rats, and the CD45RC^low subpopulation in BN rats. In this study, we found that the antiinflammatory cytokines, IL-4, IL-10, and IL-13, are exclusively produced by the CD45RC^low CD4 T cells. Using bone marrow chimeras, we showed that the difference in the CD45RC^high/CD45RC^low CD4 T cell ratio between naive LEW and BN rats is intrinsic to hemopoietic cells. Furthermore, a genome-wide search for loci controlling the balance between T cell subpopulations was conducted in a (LEW x BN) F₂ intercross. Genome scanning identified one quantitative trait locus on chromosome 9 (17 centiMorgan (cM); log of the odds ratio (LOD) score 3.9). In addition, two regions on chromosomes 10 (28 cM; LOD score 3.1) and 20 (40 cM; LOD ratio score 3) that contain, respectively, a cytokine gene cluster and the MHC region were suggestive for linkage. Interestingly, overlapping regions on these chromosomes have been implicated in the susceptibility to various immune-mediated disorders. The identification and functional characterization of genes in these regions controlling the CD45RC^high/CD45RC^low Th cell subpopulations may shed light on key regulatory mechanisms of pathogenic immune responses.

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