Repertoire Requirements of CD4+ T Cells That Prevent Spontaneous Autoimmune Encephalomyelitis

496

395

The mechanisms by which the immune system achieves constant T cell numbers throughout life, thereby controlling autoaggressive cell expansions, are to date not completely understood. Here, we show that the CD25+ subpopulation of naturally activated (CD45RBlow) CD4 T cells, but not CD25− CD45RBlow CD4 T cells, inhibits the accumulation of cotransferred CD45RBhigh CD4 T cells in lymphocyte-deficient mice. However, both CD25+ and CD25− CD45RBlow CD4 T cell subpopulations contain regulatory cells, since they can prevent naive CD4 T cell-induced wasting disease. In the absence of a correlation between disease and the number of recovered CD4+ cells, we conclude that expansion control and disease prevention are largely independent processes. CD25+ CD45RBlow CD4 T cells from IL-10-deficient mice do not protect from disease. They accumulate to a higher cell number and cannot prevent the expansion of CD45RBhigh CD4 T cells upon transfer compared with their wild-type counterparts. Although CD25+ CD45RBlow CD4 T cells are capable of expanding when transferred in vivo, they reach a homeostatic equilibrium at lower cell numbers than CD25− CD45RBlow or CD45RBhigh CD4 T cells. We conclude that CD25+ CD45RBlow CD4 T cells from nonmanipulated mice control the number of peripheral CD4 T cells through a mechanism involving the production of IL-10 by regulatory T cells.

“…However, there is increasing evidence that regulatory CD4 T cells exist in the CD25 Ϫ compartment as well (35,36). Our data showing the capacity of the CD25 Ϫ FIGURE 6.…”

Section: Discussionmentioning

confidence: 75%

CD25+ CD4+ T Cells Regulate the Expansion of Peripheral CD4 T Cells Through the Production of IL-10

Annacker

Pimenta-Araujo

Burlen-Defranoux

et al. 2001

496

395

“…Thus, it appears that the normal immune repertoire is composed of potentially autoreactive Th as well as inhibitory T cells (Fig. 4C) (35,42,43) and inhibitory T cells expand whenever there is an impending danger of pathologic autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

Induction of Autoantibody Production Is Limited in Nonautoimmune Mice

Singh

Ebling

Albuquerque

et al. 2002

Many individuals develop a single or a few brief episodes of autoimmunity from which they recover. Mechanisms that quell pathologic autoimmunity following such a breakdown of self-tolerance are not clearly understood. In this study, we show that in nonautoimmune mice, dsDNA-specific autoreactive B cells exist but remain inactive. This state of inactivation in dsDNA-specific B cells could be disrupted by autoreactive Th cells; in this case T cells that react with peptides from the VH region of anti-DNA Abs (hereafter called anti-VH T cells). Immunization with anti-DNA mAb, its γ-chain or peptides derived from its VH region induced anti-VH Th cells, IgG anti-dsDNA Ab, and proteinuria. The breakdown of B cell tolerance in nonautoimmune mice, however, was short-lived: anti-DNA Ab and nephritis subsided despite subsequent immunizations. The recovery from autoimmunity temporally correlated with the appearance of T cells that inhibited anti-DNA Ab production. Such inhibitory T cells secreted TGFβ; the inhibition of anti-DNA Ab production by these cells was partly abolished by anti-TGFβ Ab. Even without immunization, nonautoimmune mice possess T cells that can inhibit autoantibody production. Thus, inhibitory T cells in nonautoimmune mice may normally inhibit T-dependent activation of autoreactive B cells and/or reverse such activation following stimulation by Th cells. The induction of such inhibitory T cells may play a role in protecting nonautoimmune mice from developing chronic autoimmunity.

“…Only a ␣␤ ϩ T cell population possessed effective regulatory activity. Additional studies have shown that the regulatory cells that prevent spontaneous EAE in this model are CD4 ϩ T cells expressing a diverse T cell repertoire (27).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Experimental Autoimmune Encephalomyelitis in the C57BL/6J Mouse by NK1.1+, DX5+, αβ+ T Cells

Fritz

Zhao

2001

C57BL/6 (B6) mice with targeted mutations of immune function genes were used to investigate the mechanism of recovery from experimental autoimmune encephalomyelitis (EAE). The acute phase of passive EAE in the B6 mouse is normally resolved by partial recovery followed by mild sporadic relapses. B6 TCR β-chain knockout (KO) recipients of a myelin oligodendrocyte glycoprotein p35–55 encephalitogenic T cell line failed to recover from the acute phase of passive EAE. In comparison with wild-type mice, active disease was more severe in β2-microglobulin KO mice. Reconstitution of TCR β-chain KO mice with wild-type spleen cells halted progression of disease and favored recovery. Spleen cells from T cell-deficient mice, IL-7R KO mice, or IFN-γ KO mice were ineffective in this regard. Irradiation or treatment of wild-type spleen cell population with anti-NK1.1 mAb before transfer abrogated the protective effect. Removal of DX5+ cells from wild-type spleen cells by anti-DX5 Ab-coated magnetic beads before reconstitution abrogated the suppressive properties of the spleen cells. TCR-deficient recipients of the enriched DX5+ cell population recovered normally from passively induced acute disease. DX5+ cells were sorted by FACS into DX5+ αβTCR+ and DX5+ αβTCR− populations. Only recipients of the former recovered normally from clinical disease. These results indicate that recovery from acute EAE is an active process that requires NK1.1+, DX5+ αβ+ TCR spleen cells and IFN-γ.