In Vivo CD4+ T Cell Tolerance Induction Versus Priming Is Independent of the Rate and Number of Cell Divisions

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.

Section: Discussionsupporting

confidence: 53%

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

“…Mice, adoptive transfer, and flow cytometry C3-HA low (5) and C3-HA high (30) transgenic mice that express influenza HA as a parenchymal self-Ag on both the B10.D2 (H-2 d ) and B6 (H-2 b ) Thy1.2 ϩ backgrounds as well as 6.5-transgenic mice expressing a TCR specific for an I-E d -restricted HA epitope (31) that have been backcrossed to the B10.D2 Thy1.1 ϩ background have previously been described. CD11c-DTR-transgenic mice (9) were backcrossed from the B6 to the B10.D2 Thy1.2 ϩ background.…”

Section: Methodsmentioning

confidence: 99%

“…When naive clonotypic HA-specific TCR-transgenic CD4 cells are adoptively transferred into C3-HA recipients expressing either high (C3-HA high ) or low (C3-HA low ) levels of parenchymal HA, they undergo an initial proliferative response (albeit proliferation is more robust in C3-HA high recipients), followed by the development of a tolerant phenotype marked by an impaired ability to undergo further Ag-induced proliferation and to express cytokines such as IL-2, IFN-␥, and TNF-␣ (5,23,30,36). Clonotypic CD4 cells that are initially primed by viral Ag to differentiate into Th1 effectors also develop impaired function after adoptive retransfer into C3-HA recipients (24), with a particularly rapid loss in their ability to express IFN-␥ and TNF-␣ (25).…”

Section: Role Of DC In Presenting Parenchymal Self-and Viral Ag To Namentioning

confidence: 99%

Steady State Dendritic Cells Present Parenchymal Self-Antigen and Contribute to, but Are Not Essential for, Tolerization of Naive and Th1 Effector CD4 Cells

Hagymasi

Slaiby

Mihalyo

et al. 2007

Self Cite

Bone marrow-derived APC are critical for both priming effector/memory T cell responses to pathogens and inducing peripheral tolerance in self-reactive T cells. In particular, dendritic cells (DC) can acquire peripheral self-Ags under steady state conditions and are thought to present them to cognate T cells in a default tolerogenic manner, whereas exposure to pathogen-associated inflammatory mediators during the acquisition of pathogen-derived Ags appears to reprogram DCs to prime effector and memory T cell function. Recent studies have confirmed the critical role of DCs in priming CD8 cell effector responses to certain pathogens, although the necessity of steady state DCs in programming T cell tolerance to peripheral self-Ags has not been directly tested. In the current study, the role of steady state DCs in programming self-reactive CD4 cell peripheral tolerance was assessed by combining the CD11c-diphtheria toxin receptor transgenic system, in which DC can be depleted via treatment with diphtheria toxin, with a TCR-transgenic adoptive transfer system in which either naive or Th1 effector CD4 cells are induced to undergo tolerization after exposure to cognate parenchymally derived self-Ag. Although steady state DCs present parenchymal self-Ag and contribute to the tolerization of cognate naive and Th1 effector CD4 cells, they are not essential, indicating the involvement of a non-DC tolerogenic APC population(s). Tolerogenic APCs, however, do not require the cooperation of CD4+CD25+ regulatory T cells. Similarly, DC were required for maximal priming of naive CD4 cells to vaccinia viral-Ag, but priming could still occur in the absence of DC.

“…In these models, IL-2 production and T cell proliferation were impaired upon superantigen rechallenge. More recently, the availability of TCR transgenic (Tg) 5 mice has allowed the development of other in vivo models of anergy involving either administration of soluble peptide Ag (5,6) or double-Tg adoptive transfer models (7)(8)(9)(10)(11). As these recent models have been more carefully examined, however, it has become clear that in vivo anergy has a number of characteristics that are distinct from those of T cell clonal anergy.…”

mentioning

confidence: 99%

Adaptive Tolerance and Clonal Anergy Are Distinct Biochemical States

Chiodetti

Choi

Barber

et al. 2006

Adaptive tolerance is a process by which T cells become desensitized when Ag stimulation persists following an initial immune response in vivo. To examine the biochemical changes in TCR signaling present in this state, we used a mouse model in which Rag2−/− TCR-transgenic CD4+ T cells were transferred into CD3ε−/− recipients expressing their cognate Ag. Compared with naive T cells, adaptively tolerant T cells had normal levels of TCR and slightly increased levels of CD4. Following activation with anti-TCR and anti-CD4 mAbs, the predominant signaling block in the tolerant cells was at the level of Zap70 kinase activity, which was decreased 75% in vitro. Phosphorylations of the Zap70 substrates (linker of activated T cells and phospholipase Cγ1 were also profoundly diminished. This proximal defect impacted mostly on the calcium/NFAT and NF-κB pathways, with only a modest decrease in ERK1/2 phosphorylation. This state was contrasted with T cell clonal anergy in which the RAS/MAPK pathway was preferentially impaired and there was much less inhibition of Zap70 kinase activity. Both hyporesponsive states manifested a block in IκB degradation. These results demonstrate that T cell adaptive tolerance and clonal anergy are distinct biochemical states, possibly providing T cells with two molecular mechanisms to curtail responsiveness in different biological circumstances.