The Suppression of Murine Lupus by a Tolerogenic Peptide Involves Foxp3-Expressing CD8 Cells That Are Required for the Optimal Induction and Function of Foxp3-Expressing CD4 Cells

Abstract

A peptide, designated human CDR1 (hCDR1), that is based on the CDR1 of an anti-DNA Ab ameliorates systemic lupus erythematosus (SLE) in murine models via the induction of CD4+CD25+ regulatory T cells (Tregs). In the present study, the involvement of CD8 Tregs in the mode of action of hCDR1 was investigated in SLE-afflicted (NZB × NZW)F1 mice and in SJL mice following immunization with the lupus-inducing anti-DNA mAb that bears a common Id, 16/6Id. Treatment with hCDR1 up-regulated Foxp3-expressing CD8+CD28− Tregs in association with clinical amelioration of lupus manifestations. Furthermore, the in vivo depletion of the latter cells diminished the clinical improvement and the inhibitory effects of hCDR1 on the secretion of IFN-γ and resulted in the up-regulation of IL-10. However, the stimulatory effect of hCDR1 on the secretion of TGF-β was not affected by the CD8 Tregs. In the absence of CD8 Tregs, CD4+CD25+ Tregs were unable to expand in the hCDR1-treated mice, and the expression of Foxp3 was reduced, thereby interfering further with the suppressive function of CD4+CD25+ Tregs as determined in the in vitro assays. However, CD8 cells from hCDR1-treated mice that were adoptively transferred into SLE-afflicted mice led to up-regulation of CD4+CD25+ cells with intensified Foxp3 expression in the recipient mice. Thus, a functional link between two subsets of Tregs is demonstrated in which CD8+CD28− Tregs are required for both the optimal expansion and function of lupus ameliorating hCDR1-induced CD4+CD25+ Tregs.

Antigen Specificity Is not Required for Modulation of Lung Allergic Responses by Naturally Occurring Regulatory T Cells

“…Recent data confirmed the role of CD8 ϩ T cells in activating the suppressive program of CD4 ϩ CD25 ϩ T cells in a different mouse (C57BL/6) model (36). In the present study, we determined whether or not the same mechanism of activation of OVA-CD4 ϩ CD25 ϩ T cells occurs in BALB/c mice sensitized and challenged with the unrelated allergen RW.…”

“…This role for CD8 was recently supported by data suggesting that CD8 ϩ T cells enhanced the regulatory function of CD4 ϩ CD25 ϩ T cells in a different animal model (36). We investigated the effects of in vitro treatment of OVA-CD4 ϩ CD25 ϩ T cells with anti-MHC I or administration of anti-CD8␤ by microspray, before intratracheal transfer of OVA-CD4 ϩ CD25 ϩ T cells in RW sensitized and challenged mice.…”

“…The important role of CD8 ϩ T cells in the development of lung allergic responses has been demonstrated by their depletion in sensitized and challenged WT mice resulting in lower AHR and inflammation (9), and reconstitution with primed but not naive CD8 ϩ T cells or differentiated CD8 ϩ effector memory T cells in sensitized and challenged CD8 Ϫ/Ϫ recipients (12,20). CD8 expression has also been implicated in the activation of the suppressive program of nTregs (36). In the absence of any obvious Ag specificity, adoptive transfer of nTregs from naive donors suppressed AHR and inflammation in recipients reconstituted with negatively but not positively selected primed CD8 ϩ T cells (20).…”

IFN-γ–Producing Effector CD8 T Lymphocytes Cause Immune Glomerular Injury by Recognizing Antigen Presented as Immune Complex on Target Tissue

“…26). In previous studies, the phenotype of inhibitory CD8 Tregs was shown to fluctuate (37)(38)(39)(40). Inhibitory CD8 Treg function was reported to be defective in human SLE patients and in animal models of SLE (41)(42)(43).…”

TLR2 Agonists Enhance CD8+Foxp3+ Regulatory T Cells and Suppress Th2 Immune Responses during Allergen Immunotherapy

“…CD8 + Treg cells were first identified in human tonsils; upon in vitro activation, Foxp3 + CD8 + Treg cells were shown to inhibit T cell proliferation directly (12). CD8 + Treg cells seem to perform a regulatory function that limits autoimmune disease in several experimental models (17,31,32). Systemic immunization with allergen in mice induces CD8 + Treg cells that can inhibit the development of allergic diarrhea, suggesting that CD8 + Treg cells may play a pivotal role in limiting allergic disease (33).…”