The immune system contains natural regulatory T cells that control the magnitude of the immune response during physiologic and pathologic conditions. Although this suppressive function was historically attributed to CD8 T cells, most recent reports have focused on natural regulatory CD4 T cells. In the present study, we describe a new subset of natural CD8 regulatory T cells in normal healthy animals. This subset expresses low levels of CD45RC at its surface (CD45RC low ); produces mainly interleukin-4 (IL-4), IL-10, and IL-13 cytokines upon in vitro stimulation; expresses Foxp3 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4); and is not cytotoxic against allogeneic targets. This subset suppresses the proliferation and differentiation of autologous CD4 T cells into type-1 cytokines producing T cells after stimulation with allogeneic accessory cells. We also provide evidence that this regulatory subset mediates its suppression by cell-to-cell contact and not through secretion of suppressive cytokines. Finally, the regulatory activity of CD8 CD45RC low cells is also demonstrated in vivo in a rat model of CD4-dependent graft-versus-host disease. Collectively, these data demonstrate for the first time that freshly isolated rat CD8 CD45RC low T cells contain T cells with regulatory properties, a result that enlarges the general picture of T-cell-mediated regulation. (
IntroductionThe delicate balance between pathogen-induced effector immunologic functions and natural self-tolerance mechanisms is of vital importance for preserving the integrity of a host in the course of an immune response. In different species of rodents and in humans, there is compelling evidence that the regulation of the magnitude of protective immunity to foreign antigens as well as the control of autoaggressive immune reactions are ensured by regulatory CD4 and CD8 T lymphocytes that display anti-inflammatory and antiproliferative functions. Convergent evidence indicates that multiple subtypes of regulatory T cells exist and that their regulatory activities are mediated either by immunosuppressive cytokines or by contact-dependent mechanisms. [1][2][3][4][5][6][7][8] CD45 is a transmembrane tyrosine phosphatase expressed as isoforms of different molecular weight, which result in the differential splicing of 3 exons (A, B, and C) encoding part of the N-terminal extracellular domain. In the rat, CD45RC expression levels define 2 subpopulations of CD4 T cells with different cytokine profiles and functions. 3,[9][10][11][12] Functional analyses of CD45RC high and CD45RC low CD4 T cells have demonstrated that important regulatory interactions occur between these subsets in vivo. 11,13,14 For example, the adoptive transfer of CD45RC high CD4 T cells from congenic euthymic donors to nude rats induces a fatal wasting disease, while the transfer of both subpopulations, or of the CD45RC low cells alone, has no effect. 11 Similar results were obtained using mouse CD4 T cells fractionated on the basis of CD45RB expression. 15 It has also been demo...