CD4+ T-cell responses to self-peptide–MHC (original) (raw)
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Immunity, 2002
Branch the periphery at much higher levels than in the thymus. National Cancer Institute In addition, mature T cells express 5-to 10-fold more 2 Veterinary Resources Program surface TCR than their DP thymocyte precursors (Robey National Institutes of Health and Fowlkes, 1994). As a consequence, interactions be-Bethesda, Maryland 20892 tween TCR and self-MHC/peptide complexes that were 3 Transplantation Unit of low avidity in the thymus may translate into signifi-Massachusetts General Hospital cantly higher avidity interactions in the periphery. Boston, Massachusetts 02114 Two different mechanisms have been offered as po-4 Division of Therapeutic Proteins and tential explanations for why autoimmunity usually does 5 Laboratory of Pediatric and Respiratory not occur. One proposal, which we will refer to as "tun-Viral Diseases ing," posits that the activation threshold of mature T Food and Drug Administration cells is not fixed but is dynamically regulated by encoun-Bethesda, Maryland 20892 ters with self-MHC/peptide complexes in the periphery
Proceedings of the National Academy of Sciences, 2006
Differences in T cell receptor (TCR) signaling initiated by interactions among TCRs, coreceptors, and self-peptide–MHC complexes determine the outcome of CD4 versus CD8 lineage of T cell differentiation. The H-2L d and K bm3 alloreactive 2C TCR is positively selected by MHC class I K b and a yet-to-be identified nonclassical class I molecule to differentiate into CD8 + T cells. Here we describe two mechanisms by which CD4 + 2C T cells can be generated in 2C TCR-transgenic mice. In the RAG −/− background, development of CD4 + 2C T cells requires the expression of both I-A b and the TAP genes, indicating that both MHC class I and II molecules are required for positive selection of these T cells. Notably, only some of the 2C + RAG −/− mice (≈30%) develop CD4 + 2C T cells, with frequencies in individual mice varying from 0.5% to as high as ≈50%. In the RAG + background, where endogenous TCRα genes are rearranged and expressed, CD4 + 2C T cells are generated because these cells express t...
Potent effects of low levels of MHC class II-associated invariant chain on CD4+ T cell development
Immunity, 1995
Invariant chain (Ii)-negative mice exhibit defects in MHC class II assembly and transport that results in reduced levels of surface class II, altered antigen presentation, and inefficient positive selection of CD4+ T cells. Many CD4+ T cells that do mature in Ii-negative mice express a cell surface phenotype consistent with aberrant positive selection or peripheral activation. Reconstitution of these mice with low levels of either the p31 or p41 form of Ii does not restore transport of the bulk of class II or class II surface expression, but surprisingly does restore positive selection as measured by numbers and surface phenotype of CD4+ T cells. Thus, an Ii-dependent process, independent of effects on class II surface density, appears to be required for normal positive selection of CD4+ T cells.
Function and regulation of MHC class II molecules in T-lymphocytes: of mice and men
Human Immunology, 2004
The main function of major histocompatibility complex (MHC) class II molecules is to present processed antigens, which are derived primarily from exogenous sources, to CD4 ϩ T-lymphocytes. MHC class II molecules thereby are critical for the initiation of the antigen-specific immune response. Besides antigen presentation, growing evidence is showing that ligation of MHC class II molecules also activates intracellular signaling pathways, frequently leading to apoptosis. Constitutive expression of MHC class II molecules is confined to professional antigen-presenting cells (APC) of the immune system, and in nonprofessional APCs MHC class II molecules can be induced by a variety of immune regulators. Interestingly, activated T cells from many species, with the exception of mice, synthesize and express MHC class II molecules at their cell surface. In this review, we discuss our current knowledge on the transcriptional regulation of MHC class II expression in activated human and mouse T cells, and the contribution of DNA methylation of the T-cell employed class II transactivator promoter III to the MHC class II deficiency of mouse T cells. We also discuss the proposed functions of the activated T cell synthesized and expressed MHC class II molecules, including antigen presentation, T-T cell interactions, and MHC class II-mediated intracellular signaling. Human Immunology 65, 282-290 (2004).
MHC control of CD4+ T cell subset activation
Journal of Experimental Medicine, 1989
The present results demonstrate that CD4+ T cells activated in the primary in vivo response to antigen produce distinct patterns of cytokines depending upon the MHC class II haplotype of the responding mice. I-As mice were found to selectively activate IL-2/IFN-gamma-producing CD4+ T cells, whereas I-Ab mice exhibited selective activation of IL-4-producing CD4+ T cells in response to collagen IV. The effector response phenotype was found to correlate with the cytokine phenotype of CD4+ T cells activated in vivo; IL-2/IFN-gamma-producing cells giving rise to proliferative (cell-mediated) responses, IL-4-producing cells leading to secondary IgG (humoral) responses. Together the data support the notion that the outcome of a given immune response (e.g., protection vs. onset, tolerance vs. autoimmunity) may be determined in part by the type of CD4+ T cells initially activated by antigen. Moreover, the present experiments demonstrate for the first time that polymorphism in class II MHC ca...
MHC-dependent survival of naïve T cells? A complicated answer to a simple question
Microbes and Infection, 2002
The differentiation and survival of developing α thymocytes depends on effective T-cell receptor (TCR) signaling upon recognition of self peptide/major histocompatibility complex (MHC) molecule ligands. Although this concept is uniformly accepted with regard to immature thymocytes, there are conflicting reports as to whether or not MHC recognition is required for survival of mature peripheral naïve T cells. In this review, we assess these reports critically and conclude that in many cases, the differences observed in CD4 + T-cell recovery between MHC-expressing and MHC-deficient animals can be attributed to proliferation occurring only in the MHC-expressing lymphopenic animals studied in these models systems, rather than to effects of MHC recognition on cell viability per se. Still other reports involve experimental manipulations that may have affected the intrathymic development of the T cells such that they receive a "poor" selecting signal, fail to fully mature, and thus behave more like thymocytes in their survival characteristics (i.e., show MHC dependence). With respect to CD8 + T cells, we discuss data suggesting that some clones are more dependent upon the presence of MHC class I for survival than others. We propose that some CD8 + T cells even in a wild-type host may behave like the manipulated CD4 + T cells just described, and fail to mature completely with respect to their survival requirements. Although the proportion of CD8 + cells in this MHC-dependent state is not known, the corresponding fraction among CD4 + T cells seems to be rather small. Overall, our analysis of the available data suggests that most or all mature CD4 + (and perhaps also many CD8 + ) T lymphocytes do not depend on self-recognition for their viability in the periphery. Published by É ditions scientifiques et médicales Elsevier SAS.
Immunity, 1996
atrophies after puberty and plays little role in the mainte-and Takeyuki Shimizu* nance of the T cell pool in secondary lymphoid organs *Basel Institute for Immunology (Sprent, 1993). In fact, the turnover of mature T cells is Grenzacherstrasse 487 not detectably affected by adult thymectomy (Tough CH-4005 Basel and Sprent, 1994), and a peripheral T cell pool is main-Switzerland tained in a self-renewing manner by cell division and † F. Hoffmann-La Roche Ltd. cell death. Naive T cells, which have not encountered CH-4070 Basel antigens, can survive for prolonged periods and are able Switzerland to mount primary responses to new antigens in advanced age (Bruno et al., 1995). In addition, TCR V␣ and V usages of CD4 ϩ T cells do not change with age, Summary suggesting that the TCR repertoire of CD4 ϩ T cells remains constant with age (Callahan et al., 1993). Since We grafted fetal thymi from wild-type mice into immuthe total number of cells in lymphoid organs is relatively nodeficient RAG-2 Ϫ/Ϫ or class II Ϫ/Ϫ RAG-2 Ϫ/Ϫ (class II constant, dividing T cell clones would dilute out resting MHC Ϫ) recipients and followed the fate of naive CD4 ؉ T cell clones. It is thus surprising that enormous diversity T cells derived from the grafts. In both types of recipiof the TCR repertoire is maintained for extended peents, newly generated CD4 ؉ T cells proliferated to the riods. same extent in the periphery and rapidly filled the It is not clear whether T cells can divide in vivo without empty T cell compartment. However, CD4 ؉ T cells in signaling through the TCR. The activation of mature class II Ϫ recipients gradually decreased in number over CD4 ϩ T cells in vivo generally results from the binding 6 months. These results show that interactions beof the TCR to specific immunogenic peptides embedded tween the TCR and class II molecules are not required in MHC class II molecules, which are expressed mainly for newly generated CD4 ؉ T cells to survive and prolifon professional antigen-presenting cells in the peripherate, but are necessary to maintain the size of the ery. Similarly, it is believed that TCR-mediated signals peripheral T cell pool for extended periods. are required for the proliferation of T cell clones in vitro. However, the following observations suggest that sig
BMC biology, 2014
BackgroundAs individual naïve CD4 T lymphocytes circulate in the body after emerging from the thymus, they are likely to have individually varying microenvironmental interactions even in the absence of stimulation via specific target recognition. It is not clear if these interactions result in alterations in their activation, survival and effector programming. Naïve CD4 T cells show unimodal distribution for many phenotypic properties, suggesting that the variation is caused by intrinsic stochasticity, although underlying variation due to subsets created by different histories of microenvironmental interactions remains possible. To explore this possibility, we began examining the phenotype and functionality of naïve CD4 T cells differing in a basic unimodally distributed property, the CD4 levels, as well as the causal origin of these differences.ResultsWe examined separated CD4hi and CD4lo subsets of mouse naïve CD4 cells. CD4lo cells were smaller with higher CD5 levels and lower le...