Anti-TCR Antibody Treatment Activates a Novel Population of Nonintestinal CD8αα+TCRαβ+ Regulatory T Cells and Prevents Experimental Autoimmune Encephalomyelitis

Abstract

CD8αα+CD4−TCRαβ+ T cells are a special lineage of T cells found predominantly within the intestine as intraepithelial lymphocytes and have been shown to be involved in the maintenance of immune homeostasis. Although these cells are independent of classical MHC class I (class Ia) molecules, their origin and function in peripheral lymphoid tissues are unknown. We have recently identified a novel subset of nonintestinal CD8αα+CD4−TCRαβ+ regulatory T cells (CD8αα Tregs) that recognize a TCR peptide from the conserved CDR2 region of the TCR Vβ8.2-chain in the context of a class Ib molecule, Qa-1a, and control- activated Vβ8.2+ T cells mediating experimental autoimmune encephalomyelitis. Using flow cytometry, spectratyping, and real-time PCR analysis of T cell clones and short-term lines, we have determined the TCR repertoire of the CD8αα regulatory T cells (Tregs) and found that they predominantly use the TCR Vβ6 gene segment. In vivo injection of anti-TCR Vβ6 mAb results in activation of the CD8αα Tregs, inhibition of the Th1-like pathogenic response to the immunizing Ag, and protection from experimental autoimmune encephalomyelitis. These data suggest that activation of the CD8αα Tregs present in peripheral lymphoid organs other than the gut can be exploited for the control of T cell-mediated autoimmune diseases.

CD8+Foxp3+ T cells share developmental and phenotypic features with classical CD4+Foxp3+ regulatory T cells but lack potent suppressive activity

“…The vast majority of Foxp3 1 T cells are confined to TCR-ab 1 CD4 1 T cells, and little is known about CD8 1 T cells expressing Foxp3. Certain surface phenotypes such as CD28 À [7], CD122 1 [8], CD8aa 1 [9,10], latencyassociated peptide (LAP) 1 [11] and restriction to the nonclassical MHCI molecule Qa-1 [12] have been linked with immunosuppressive functions of CD8 1 T cells. However, Foxp3 expression was either absent in these populations [8,9,[13][14][15], incongruent with the defining surface phenotype [11] or was not investigated specifically on a protein level [16].…”

Dendritic Cells Use Endocytic Pathway for Cross-Priming Class Ib MHC-Restricted CD8αα+TCRαβ+ T Cells with Regulatory Properties

“…ϩ intraepithelial lymphocyte population in that they both express the CD8␣␣ ϩ homodimer that can bind TL tetramers (18,19). Class Ib MHC molecules appear to play an important role in the development or survival of CD8␣␣ ϩ TCR␣␤ ϩ intraepithelial lymphocytes; these cells are present in mice lacking class Ia MHC and CD1 molecules (20 -23).…”

“…ϩ TCR␣␤ ϩ T cell clones and lines (11,17,18). These cells are physiologically primed and are involved in recovery from EAE induced by the myelin basic protein (MBP) acetylated N-terminal peptide Ac1-9, designated throughout as MBP(Ac1-9).…”

“…MHC class Ib-restricted T cells are distinct from MHC class Ia-restricted T cells in that they behave like innate lymphocytes in the following ways: 1) they generally have an activated phenotype and are CD44 high ; 2) they are selected by hematopoietic cells (14), 3) they can be activated in the periphery by their thymic selecting ligand/agonist; 4) they rapidly produce cytokines upon activation (15); and 5) their gene expression phenotype has special features differing from that of adaptive T cells (16). Recently, we have described a peripheral subset of MHC class Ib-restricted CD8␣␣ ϩ TCR␣␤ ϩ T cells that control experimental autoimmune encephalomyelitis (EAE) 4 by killing disease-mediating CD4 ϩ T cells in an Ag-specific manner (11,17,18). These T cells appear to have similarities with the gut-residing CD8␣␣ ϩ…”

Immunodominance in the TCR Repertoire of αTCR Peptide-Specific CD4+ Treg Population That Controls Experimental Autoimmune Encephalomyelitis

“…In contrast to the CD25 ϩ CD4 ϩ Treg, our sequence data indicate no overlap in the TCR repertoires of the pathogenic and Treg populations. The other essential regulatory arm in the B10.PL system, residing within the CD8 ϩ subset (4, 38), is an upstream determinant of the ϩ Treg population is also restricted, resulting in limited TCR diversity within each of the three relevant T cell populations in this system (41).…”