CD4+ T Cell Tolerance to Parenchymal Self-Antigens Requires Presentation by Bone Marrow–derived Antigen-presenting Cells

Abstract

T cell tolerance to parenchymal self-antigens is thought to be induced by encounter of the T cell with its cognate peptide–major histocompatibility complex (MHC) ligand expressed on the parenchymal cell, which lacks appropriate costimulatory function. We have used a model system in which naive T cell receptor (TCR) transgenic hemagglutinin (HA)-specific CD4+ T cells are adoptively transferred into mice expressing HA as a self-antigen on parenchymal cells. After transfer, HA-specific T cells develop a phenotype indicative of TCR engagement and are rendered functionally tolerant. However, T cell tolerance is not induced by peptide–MHC complexes expressed on parenchymal cells. Rather, tolerance induction requires that HA is presented by bone marrow (BM)–derived cells. These results indicate that tolerance induction to parenchymal self-antigens requires transfer to a BM-derived antigen-presenting cell that presents it to T cells in a tolerogenic fashion.

Granulocytes mediates the Fas-L-associated apoptosis during lung metastasis of melanoma that determines the metastatic behaviour

“…Depletions of CD4 + or CD8 + cells did not affect (clone V3) or even slightly inhibit (clone V4) the progression of tumours having high Fas-L. Recent studies have also demonstrated that T cells specific for tumour antigens can become actively tolerated during progression of tumours (Mackensen et al, 1993;Adler et al, 1998). It is possible that altered T cells may produce a distinct profile of cytokine productions, which in turn stimulate tumour formation (Medvedev et al, 1997;Mori et al, 1997).…”

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

“…2B). At day ϩ5, these clonotypic CD4 cells were no longer undergoing cell cycle progression as indicated by a lack of blastogenesis (data not shown) despite the continual presence of the transgenically expressed Ags that initiated the transient proliferative response, however, indicating that they had developed an anergic or nonresponsive phenotype (5,24). This nonresponsive state was further illustrated by the severely impaired ability of these self-Ag-exposed clonotypic CD4 cells to express intracellular TNF-␣ (a sensitive indicator of tolerization; see Refs.…”

“…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).…”

“…In the current study, we assessed the role of DC in inducing tolerization and priming of naive and effector CD4 cells by combining our previously established system in which naive (5,23) or Th1 effector (24,25) TCR-transgenic hemagglutinin (HA)-specific clonotypic CD4 cells are tolerized or primed following adoptive transfer into recipients that express HA either as a parenchymal self-Ag or a recombinant vaccinia viral Ag, respectively, with the CD11c-diphtheria toxin receptor (DTR) transgenic system in which DC can be depleted via treatment with diphtheria toxin (DT; Ref. 9).…”

“…Owing to their efficiency in capturing and presenting exogenous Ags as well as their abilities both to express critical costimulatory ligands and to interact with naive T cells in secondary lymphoid organs, a large body of literature has suggested that dendritic cells (DC) 5 are the principal APC population that primes effector/memory T cell responses to pathogen-derived Ags (reviewed in Refs. 7 and 8).…”