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1.
Clonotype‐specific avidity influences the dynamics and hierarchy of virus‐specific regulatory and effector CD4+ T‐cell responses
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Jie Liu Shirley Cao Gretchen Peppers Sung‐Han Kim Barney S. Graham 《European journal of immunology》2014,44(4):1058-1068
A key component of immunity against viruses, CD4+ T cells expand and differentiate into functional subsets upon primary infection, where effector (Teff) cells facilitate infection control and regulatory (Treg) cells mitigate immunopathology. After secondary infection, Teff cells mount a robust response from the memory pool. Here, we show that Treg‐cell responses are diminished upon secondary infection, and Treg‐cell response dynamics are associated more with T‐cell receptors (TCRs) repertoire and avidity than with epitope specificity. In the murine model, the IAbM209 epitope of respiratory syncytial virus is recognized by both CD4+ Treg and Teff cells, while the IAbM226 epitope is recognized almost exclusively by CD4+ Teff cells expressing high avidity TCR Vβ8.1/8.2 and dominating the CD4+ T‐cell response during primary and secondary infections. IAbM209‐Teff cells express relatively low avidity TCRs during early primary infection, but high avidity TCR Vβ7‐expressing IAbM209‐Teff cells emerge during the late phase, and become dominant after secondary infection. The emerging high avidity IAbM209‐Teff cells outcompete IAbM209‐Treg cells that share the same epitope, but have low avidity and are restricted to TCR Vβ2 and Vβ6 subpopulations. These data indicate that MHC‐peptide‐TCR interactions can produce different kinetic and functional profiles in CD4+ T‐cell populations even when responding to the same epitope. 相似文献
2.
CD8 T cells that recognize cytomegalovirus (CMV) ‐encoded peptides can be readily detected by staining with human leucocyte antigen (HLA) –peptide tetramers. These cells are invariably highly differentiated effector memory cells with high avidity T‐cell receptors (TCR). In this report we demonstrate an HLA‐A*0201 restricted CMV‐specific CD8 T‐cell response (designated YVL) that represents several percent of the CD8 T‐cell subset, yet fails to bind tetrameric major histocompatibility complex (MHC) ligands. However, these tetramer‐negative cells are both phenotypically and functionally similar to other CMV‐specific CD8 T cells. YVL peptide‐specific CD8 T‐cell clones were generated and found to be of high avidity in both cytotoxicity and interferon‐γ (IFN‐γ) assays, and comparable with other CMV peptide‐specific CD8 T‐cell clones. However, under conditions of CD8 blockade, the response was almost nullified even at very high ligand concentrations. This was also the case in IFN‐γ experiments using peripheral blood mononuclear cells stimulated with peptide ex vivo. In contrast, all other CMV specificities (tetramer‐positive) displayed minimal or only partial CD8 dependence. This suggests that YVL‐specific responses depict a low‐affinity TCR–MHC–peptide interaction, that is compensated by substantial CD8 involvement for functional purposes, yet cannot engage multivalent soluble ligands for ex vivo analysis. It is interesting that such a phenomenon is apparent in the face of a persistent virus infection such as CMV, where the responding cells represent an immunodominant response in that individual and may present a highly differentiated effector phenotype. 相似文献
3.
The strength of interaction between the antigenic peptide‐loaded MHC (MHC/p) and the TCR determines T‐cell fate in the thymus. A high avidity interaction between the TCR and the MHC/p induces apoptosis of self‐reactive T cells (negative selection), whereas a moderate avidity interaction rescues thymocytes from apoptosis and permits further differentiation to mature T cells (positive selection). Leukocyte common antigen‐related molecule (LAR), a receptor‐like protein tyrosine phosphatase, is expressed on immature thymocytes, but its role in thymocyte differentiation has not yet been fully elucidated. We analyzed LAR‐deficient mice and demonstrated that LAR deficiency affected the differentiation and expansion of immature thymocytes as well as positive and negative selection. Furthermore, LAR deficiency resulted in a lower Ca2+ response. The results indicate that LAR is an important modulator of TCR signaling that controls thymocyte differentiation. 相似文献
4.
Katakai T; Agata Y; Shimizu A; Ohshima C; Nishio A; Inaba M; Kasakura S; Mori KJ; Masuda T 《International immunology》1997,9(12):1849-1855
A parietal cell-specific Th1 clone, II-6, which was established from a
BALB/c mouse bearing post-thymectomy autoimmune gastritis (AIG), recognizes
a peptide of the alpha subunit (alpha891-905) of H+/K+- ATPase and induces
gastritis in nu/nu BALB/c mice by adoptive cell transfer. In the present
study, the primary structure of the TCR of II- 6 was determined as
Valpha10-Jalpha c5a-Calpha and Vbeta14-Jbeta2.3- Cbeta2 by cDNA cloning.
Using PCR with specific primers, we defined the use of this II-6 TCR in
nu/nu mice with transferred II-6 cells and in mice that spontaneously
developed AIG by thymectomy on day 3 after birth (d3-Tx). II-6 TCR mRNAs
were detected in the gastric mucosa of all of the nu/nu mice, suggesting
that II-6 cells indeed home to the gastric mucosa and thereby were directly
involved in the destruction of target parietal cells. TCR beta chain mRNAs
encoding CDR3 region sequences almost identical with that of II-6 were also
found in the gastric mucosa in 43% (six of 14 mice tested) of the d3-Tx AIG
mice at 4-12 weeks old by nested RT-PCR. Such a frequent appearance of
similar clonotypes in independent individuals suggests that T cells bearing
II- 6-like TCR including the II-6 itself might be directly involved in,
although not essential for, the pathogenesis of AIG in 3d-Tx mice.
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5.
Ben M. Illigens Akira Yamada Natalie Anosova Victor M. Dong Mohamed H. Sayegh Gilles Benichou 《European journal of immunology》2009,39(11):3000-3009
The contribution of direct and indirect alloresponses by CD4+ Th1 and Th2 cells in acute and chronic rejection of allogeneic transplants remains unclear. In the present study, we addressed this question using a transplant model in a single MHC class I‐disparate donor–recipient mouse combination. BALB/c‐dm2 (dm2) mutant mice do not express MHC class I Ld molecules and reject acutely Ld+ skin grafts from BALB/c mice. In contrast, BALB/c hearts placed in dm2 mice are permanently accepted in the absence of chronic allograft vasculopathy. In this model, CD4+ T cells are activated following recognition of a donor MHC class I determinant, Ld 61–80, presented by MHC Class II Ad molecules on donor and recipient APC. Pre‐transplantation of recipients with Ld 61–80 peptide emulsified in complete Freund's adjuvant induced a Th1 response, which accelerated the rejection of skin allografts, but it had no effect on cardiac transplants. In contrast, induction of a Th2 response to the same peptide abrogated the CD8+ cytotoxic T cells response and markedly delayed the rejection of skin allografts while it induced de novo chronic rejection of heart transplants. This shows that Th2 cells activated via indirect allorecognition can exert dual effects on acute and chronic rejection of allogeneic transplants. 相似文献
6.
Brian D. Hondowicz Amrita O. Batheja Michele H. Metzgar Antonio J. Pagán Olivia A. Perng Simone Willms Andrew J. Caton Jan Erikson 《European journal of immunology》2009,39(9):2377-2382
T‐cell recognition of peptide/MHC complexes is flexible and can lead to differential activation, but how interactions with agonist (full activation) or partial agonist (suboptimal activation) peptides can shape immune responses in vivo is not well characterized. We investigated the effect of stimulation by agonist or partial agonist ligands during initial CD4+ T‐cell priming, and subsequent T‐B‐cell cognate interactions, on antibody production by anti‐chromatin B cells. We found that autoantibody production required TCR recognition of an agonist peptide at the effector stage of B‐cell activation. However, interaction with a weak agonist ligand at this effector stage failed to promote efficient autoantibody production, even if the CD4+ T cells were fully primed by an agonist peptide. These studies suggest that the reactivity of the TCR for a target self‐peptide during CD4+ T‐B‐cell interaction can be a critical determinant in restraining anti‐chromatin autoantibody production. 相似文献
7.
Yoon‐Joong Kang Xiaosong Wang Sue‐Jane Lin Yen‐Ming Hsu Hsiu‐Ching Chang 《European journal of immunology》2010,40(3):836-848
Recognition of viral antigenic peptides bound to major histocompatibility complex class I molecules (MHCI) by TCR is critical for initiating the responses of CD8+ T cells that ultimately lead to elimination of virus‐infected cells. This antigen recognition is enhanced by the CD8 coreceptor through its interaction with the peptide‐MHCI complexes (pMHCI). Mouse CD8αβ can form two different complexes with pMHCI via either the CD8α‐ or CD8β‐dominated interaction. To understand the functional significance of these complexes in vivo, we generated Tg mice carrying a variant CD8αβ (CD8αm3β) capable of forming only the CD8β‐dominated CD8αβ/pMHCI complex. These mice show sub‐optimal thymic differentiation with reduced populations of CD8+ single‐positive thymocytes. Tg CD8+ T cells exhibit a compromised developmental capacity when competing with CD8+ T cells from B6 mice in mixed bone marrow chimera experiments. However, once these CD8+ T cells have emigrated to the peripheral lymphoid organs, they exhibit normal effector function against viral infection. Our observations indicate that, in addition to the CD8 activity conferred by CD8β‐dominated CD8αβ/pMHCI complexes, full thymocyte differentiation requires additional coreceptor activities conferred by CD8αα and/or CD8αβ with CD8α‐dominated CD8/pMHCI complexes. 相似文献
8.
Transnuclear CD8 T cells specific for the immunodominant epitope Gra6 lower acute‐phase Toxoplasma gondii burden
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Anna Sanecka Nagisa Yoshida Stephanie K. Dougan John Jackson Nilabh Shastri Hidde Ploegh Nicolas Blanchard Eva‐Maria Frickel 《Immunology》2016,149(3):270-279
We generated a CD8 T‐cell receptor (TCR) transnuclear (TN) mouse specific to the Ld‐restricted immunodominant epitope of GRA6 from Toxoplasma gondii as a source of cells to facilitate further investigation into the CD8 T‐cell‐mediated response against this pathogen. The TN T cells bound Ld‐Gra6 tetramer and proliferated upon unspecific and peptide‐specific stimulation. The TCR beta sequence of the Gra6‐specific TN CD8 T cells is identical in its V‐ and J‐region to the TCR‐β harboured by a hybridoma line generated in response to Gra6 peptide. Adoptively transferred Gra6 TN CD8 T cells proliferated upon Toxoplasma infection in vivo and exhibited an activated phenotype similar to host CD8 T cells specific to Gra6. The brain of Toxoplasma‐infected mice carried Gra6 TN cells already at day 8 post‐infection. Both Gra6 TN mice as well as adoptively transferred Gra6 TN cells were able to significantly reduce the parasite burden in the acute phase of Toxoplasma infection. Overall, the Gra6 TN mouse represents a functional tool to study the protective and immunodominant specific CD8 T‐cell response to Toxoplasma in both the acute and the chronic phases of infection. 相似文献
9.
François Legoux Laetitia Gautreau Leslie Hesnard Alexandra Leger Melinda Moyon Marie‐Claire Devilder Marc Bonneville Xavier Saulquin 《European journal of immunology》2013,43(12):3244-3253
While CD4+ T lymphocytes usually recognize antigens in the context of major histocompatibility (MHC) class II alleles, occurrence of MHC class‐I restricted CD4+ T cells has been reported sporadically. Taking advantage of a highly sensitive MHC tetramer‐based enrichment approach allowing detection and isolation of scarce Ag‐specific T cells, we performed a systematic comparative analysis of HLA‐A*0201‐restricted CD4+ and CD8+ T‐cell lines directed against several immunodominant viral or tumoral antigens. CD4+ T cells directed against every peptide‐MHC class I complexes tested were detected in all donors. These cells yielded strong cytotoxic and T helper 1 cytokine responses when incubated with HLA‐A2+ target cells carrying the relevant epitopes. HLA‐A2‐restricted CD4+ T cells were seldom expanded in immune HLA‐A2+ donors, suggesting that they are not usually engaged in in vivo immune responses against the corresponding peptide‐MHC class I complexes. However, these T cells expressed TCR of very high affinity and were expanded following ex vivo stimulation by relevant tumor cells. Therefore, we describe a versatile and efficient strategy for generation of MHC class‐I restricted T helper cells and high affinity TCR that could be used for adoptive T‐cell transfer‐ or TCR gene transfer‐based immunotherapies. 相似文献
10.
Hisakata Yamada Kensuke Shibata Koji Sakuraba Kenjiro Fujimura Yasunobu Yoshikai 《European journal of immunology》2013,43(8):2033-2042
In contrast to thymic epithelial cells, which induce the positive selection of conventional CD8+ T cells, hematopoietic cells (HCs) select innate CD8+ T cells whose Ag specificity is not fully understood. Here we show that CD8+ T cells expressing an H‐Y Ag‐specific Tg TCR were able to develop in mice in which only HCs expressed MHC class I, when HCs also expressed the H‐Y Ag. These HC‐selected self‐specific CD8+ T cells resemble innate CD8+ T cells in WT mice in terms of the expression of memory markers and effector functions, but are phenotypically distinct from the thymus‐independent CD8+ T‐cell population. The peripheral maintenance of H‐Y‐specific CD8+ T cells required presentation of the self‐Ag and IL‐15 on HCs. HC‐selected CD8+ T cells in mice lacking the Tg TCR also showed these features. Furthermore, by using MHC class I tetramers with a male Ag peptide, we found that self‐Ag‐specific CD8+ T cells in TCR non‐Tg mice could develop via HC‐induced positive selection, supporting results obtained from H‐Y TCR Tg mice. These findings indicate the presence of self‐specific CD8+ T cells that are positively selected by HCs in the peripheral T‐cell repertoire. 相似文献
11.
Nicola P. Jackson Yu Hui Kang Nicolas Lapaque Hans Janssen John Trowsdale Adrian P. Kelly 《European journal of immunology》2013,43(4):897-906
Distinct peptide‐MHC‐II complexes, recognised by Type A and B CD4+ T‐cell subsets, are generated when antigen is loaded in different intracellular compartments. Conventional Type A T cells recognize their peptide epitope regardless of the route of processing, whereas unconventional Type B T cells only recognise exogenously supplied peptide. Type B T cells are implicated in autoimmune conditions and may break tolerance by escaping negative selection. Here we show that Salmonella differentially influences presentation of antigen to Type A and B T cells. Infection of bone marrow‐derived dendritic cells (BMDCs) with Salmonella enterica serovar Typhimurium (S. Typhimurium) reduced presentation of antigen to Type A T cells but enhanced presentation of exogenous peptide to Type B T cells. Exposure to S. Typhimurium was sufficient to enhance Type B T‐cell activation. Salmonella Typhimurium infection reduced surface expression of MHC‐II, by an invariant chain‐independent trafficking mechanism, resulting in accumulation of MHC‐II in multi‐vesicular bodies. Reduced MHC‐II surface expression in S. Typhimurium‐infected BMDCs correlated with reduced antigen presentation to Type A T cells. Salmonella infection is implicated in reactive arthritis. Therefore, polarisation of antigen presentation towards a Type B response by Salmonella may be a predisposing factor in autoimmune conditions such as reactive arthritis. 相似文献
12.
Catherine L. Keech Ken C. Pang James McCluskey Weisan Chen 《European journal of immunology》2010,40(2):330-338
Controversy still surrounds the importance of cross‐presentation versus endogenous or direct presentation of MHC‐I restricted Ag in CD8+ T‐cell (TCD8+) immunity. It is even less clear what relative role these pathways play in shaping the T‐cell repertoire specific for ubiquitous self‐antigens, especially in cases where both Ag presentation pathways could potentially be involved. Here we provide evidence that a TCD8+ repertoire specific for a determinant from the nuclear autoantigen La‐SSB is largely shaped by direct presentation. In this system, mouse TCD8+ reactive to a xenogeneic human La (hLa51–58) Kb peptide did not recognize directly presented peptide on either spleen cells from hLa‐Tg mice or hLa transfected syngeneic cells. Interestingly, the same TCD8+ were activated by in vivo challenge with allogeneic APC expressing either the Tg hLa or loaded with intact recombinant hLa protein, indicating functional cross‐presentation of the hLa51–58. However, in irradiated bone marrow chimeric mice, DC expressing Tg hLa, but not WT DC that matured in hLa‐Tg mice, constitutively presented the hLa51–58 to TCD8+. These data demonstrate that although both the direct‐ and cross‐presentation pathways are potentially operative in revealing hLa51–58 to TCD8+, the TCD8+ repertoire to this determinant is shaped quantitatively according to the efficiency of Ag presentation. 相似文献
13.
CD4+CD25+Foxp3+ regulatory T (Treg) cells can undergo both thymic selection and peripheral expansion in response to self peptides that are agonists for their T cell receptors (TCR). However, the specificity by which these TCR must recognize peptide:MHC complexes to activate Treg cell function is not known. We show that CD4+CD25+Foxp3+ Treg cells can mediate suppression in response to peptides that are only weakly cross‐reactive with the self peptide that induced their formation in vivo. Moreover, suppression could be efficiently activated by peptide analogs that were inefficient at inducing CD69 up‐regulation, and that also induced little or no proliferation of naïve CD4+CD25–Foxp3– T cells expressing the same TCR. These findings provide evidence that self peptide‐specific CD4+CD25+Foxp3+ Treg cells can exert regulatory function in response to self‐ and/or pathogen‐derived peptides with which they are only weakly cross‐reactive. 相似文献
14.
Julia Goldstein Howard Mostowsky Joyce Tung Huiming Hon Mark Brunswick Steven Kozlowski 《European journal of immunology》1997,27(4):871-878
In this report, we demonstrate stimulation of T cell receptor (TCR) transgenic CD8 T cells by isolated major histocompatibility complex (MHC) class I H-2Ld complexes and antigenic peptide. This is the first demonstration of CD8 T cells activated by MHC and antigenic peptide in the absence of antigen priming. Furthermore, isolated MHC and a potent peptide antigen can stimulate phenotypically naive CD44? T cells to become CTL effectors and to produce interleukin-2 in nanogram per milliliter amounts. These results demonstrate that particular TCR antigen pairs may overcome the need for specialized antigen-presenting cells and have implications for mechanisms of autoimmunity and tolerance induction. 相似文献
15.
The T‐cell receptor (TCR) is critical for T‐cell lineage selection, antigen specificity, effector function and survival. Recently, TCR gene transfer has been developed as a reliable method to generate ex vivo large numbers of T cells of a given antigen‐specificity and functional avidity. Such approaches have major applications for the adoptive cellular therapy of viral infectious diseases, virus‐associated malignancies and cancer. TCR gene transfer utilizes retroviral or lentiviral constructs containing the gene sequences of the TCR‐α and TCR‐β chains, which have been cloned from a clonal T‐cell population of the desired antigen specificity. The TCR‐encoding vector is then used to infect (transduce) primary T cells in vitro. To generate a transduced T cell with the desired functional specificity, the introduced TCR‐α and TCR‐β chains must form a heterodimer and associate with the CD3 complex in order to be stably expressed at the T‐cell surface. In order to optimize the function of TCR‐transduced T cells, researchers in the field of TCR gene transfer have exploited many aspects of basic research in T‐cell immunology relating to TCR structure, TCR–CD3 assembly, cell‐surface TCR expression, TCR‐peptide/major histocompatibility complex (MHC) affinity and TCR signalling. However, improving the introduction of exogenous TCRs into naturally occurring T cells has provided further insights into basic T‐cell immunology. The aim of this review was to discuss the molecular immunology lessons learnt through therapeutic TCR transfer. 相似文献
16.
Generation of β cell‐specific human cytotoxic T cells by lentiviral transduction and their survival in immunodeficient human leucocyte antigen‐transgenic mice
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J. Babad G. Mukherjee A. Follenzi R. Ali B. O. Roep L. D. Shultz P. Santamaria O. O. Yang H. Goldstein D. L. Greiner T. P. DiLorenzo 《Clinical and experimental immunology》2015,179(3):398-413
Several β cell antigens recognized by T cells in the non‐obese diabetic (NOD) mouse model of type 1 diabetes (T1D) are also T cell targets in the human disease. While numerous antigen‐specific therapies prevent diabetes in NOD mice, successful translation of rodent findings to patients has been difficult. A human leucocyte antigen (HLA)‐transgenic mouse model incorporating human β cell‐specific T cells might provide a better platform for evaluating antigen‐specific therapies. The ability to study such T cells is limited by their low frequency in peripheral blood and the difficulty in obtaining islet‐infiltrating T cells from patients. We have worked to overcome this limitation by using lentiviral transduction to ‘reprogram’ primary human CD8 T cells to express three T cell receptors (TCRs) specific for a peptide derived from the β cell antigen islet‐specific glucose‐6‐phosphatase catalytic subunit‐related protein (IGRP265–273) and recognized in the context of the human class I major histocompatibility complex (MHC) molecule HLA‐A2. The TCRs bound peptide/MHC multimers with a range of avidities, but all bound with at least 10‐fold lower avidity than the anti‐viral TCR used for comparison. One exhibited antigenic recognition promiscuity. The β cell‐specific human CD8 T cells generated by lentiviral transduction with one of the TCRs released interferon (IFN)‐γ in response to antigen and exhibited cytotoxic activity against peptide‐pulsed target cells. The cells engrafted in HLA‐A2‐transgenic NOD‐scid IL2rγnull mice and could be detected in the blood, spleen and pancreas up to 5 weeks post‐transfer, suggesting the utility of this approach for the evaluation of T cell‐modulatory therapies for T1D and other T cell‐mediated autoimmune diseases. 相似文献
17.
Shohreh Issazadeh Peter Kjelln Tomas Olsson Maha Mustafa Rikard Holmdahl 《European journal of immunology》1997,27(6):1584-1587
The myelin basic protein (MBP) peptide 63–88-induced experimental autoimmune encephalomyelitis (EAE) and its associated T cell cytokine profile are influenced by the rat major histocompatibility complex (MHC). There is an allele-specific protective influence of the MHC class I region, whereas the MHC class II region display either disease-protective or -promoting effects. To investigate if the MHC-associated protection is dependent on certain combinations of MBP peptide and MHC molecules, we have now used another peptide (MBP 89–101). A broader and different set of rat MHC alleles were associated with EAE induced with MBP 89–101 as compared to MBP 63–88. All EAE-susceptible strains mounted peptide-specific strong T helper (Th) 1-like immune responses in vitro. Immunization of rats with an extended peptide (MBP 87–110) induced EAE associated with the same MHC haplotypes as the 89–101 peptide, except in LEW.1N (RT1n) rats which were relatively resistant. Only this strain responded with additional Th2-like and transforming growth factor-β responses to the peptide in vitro. In vivo depletion of CD8+ cells aggravated the disease in this strain. We conclude that both MHC-controlled promoting and protective influences on EAE are dependent on certain MHC/MBP peptide combinations, and that the 87–110 region of MBP contains a major MHC-associated encephalitogenic epitope in the rat. 相似文献
18.
Brian Vukusic Lorraine Poplonski Laurie Phillips Judy Pawling Terry Delovitch Nobumichi Hozumi Joan Wither 《Molecular immunology》1995,32(17-18)
Many autoimmune diseases are associated with specific class II MHC alleles; however, this association is not complete. One explanation for the variable expression of disease in susceptible individuals is that variability in the TCR repertoire may alter the potential to generate pathogenic autoreactive T cells. The current study was undertaken to examine the possibility that MHC and background heterozygosity, which is the norm in the outbred human population, alters the expressed TCR repertoire and, if so, whether this has an impact on peptide recognition and antigenic specificity. We, therefore, systematically analysed the beef insulin-specific TCR repertoire in inbred BALB/c mice before and after introduction of MHC heterozygosity (BALB/c × BALB.K)F1 mice, or MHC and background gene heterozygosity (BALB/c × A/J)F1 mice. We show that T cells from all three repertoires are predominantly Ad-restricted and recognize the same immunodominant peptide. Despite this, the beef insulin-specific TCR repertoires in F1 mice differ from those seen in BALB/c mice with the most dramatic changes seen in (BALB/c × A/J)F1 mice. These changes are accompanied by subtle differences in the antigenic specificity of the T cells. The results demonstrate that both MHC and background gene heterozygosity affect TCR repertoire selection, suggesting that the variable expression of autoimmune disease in individuals with a susceptible MHC allele may result, in part, from variability in the TCR repertoire introduced by this heterozygosity. 相似文献
19.
《International reviews of immunology》2013,32(5):547-573
Peptides antigens of 8 to 24 amino acid residues in length that are derived from processing of foreign proteins by antigen presenting cells (APC), and then presented to T cells in the context of major histocompatibility complex molecules (MHC) expressed by APC, are the only physiological ligands for T cell receptor (TCR). Co-ligation of TCR and CD4 co-receptor on T cells by MHC II-peptide complexes (signal 1) leads to various T cell functions depending on the nature of TCR and CD4 co-ligation, and whether costimulatory receptors (signal 2) such as CD28, CTLA-4, CD40L are involved in this interaction. Recently, the advance of genetic engineering led to the generation of a new class of antigen-specific ligands for TCR, i.e., soluble MHC class I, and MHC class II-peptide chimeras. In principle, these chimeric molecules consist of an antigenic peptide which is covalently linked to the amino terminus of α-chain in the case of MHC I, or β-chains in the case of MHC II molecules. Conceptually, such TCR/CD4 ligands shall provide the signal I to T cells. Since soluble MHC-peptide chimeras showed remarkable regulatory effects on peptide-specific T cells in vitro and in vivo, they may represent a new generation of immunospecific T cell modulators with potential therapeutic applicability in autoimmune and infectious diseases. This review is focused on the immunomodulatory effects of soluble, MHC class II-peptide chimeras, and discuss these effects in the context of the most accepted theories on T cell regulation. 相似文献
20.
γδ T cells are indispensable for interleukin‐23‐mediated protection against Concanavalin A‐induced hepatitis in hepatitis B virus transgenic mice
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《Immunology》2017,151(1):43-55
Hepatitis B virus surface antigen (HBsAg) carriers are highly susceptible to liver injury triggered by environmental biochemical stimulation. Previously, we have reported an inverse correlation between γδ T cells and liver damage in patients with hepatitis B virus (HBV). However, whether γδ T cells play a role in regulating the hypersensitivity of HBsAg carriers to biochemical stimulation‐induced hepatitis is unknown. In this study, using HBV transgenic (HBs‐Tg) and HBs‐Tg T‐cell receptor‐δ‐deficient (TCR‐δ−/−) mice, we found that mice genetically deficient in γδ T cells exhibited more severe liver damage upon Concanavalin A (Con A) treatment, as indicated by substantially higher serum alanine aminotransferase levels, further elevated interferon‐γ (IFN‐γ) levels and more extensive necrosis. γδ T‐cell deficiency resulted in elevated IFN‐γ in CD4+ T cells but not in natural killer or natural killer T cells. The depletion of CD4+ T cells and neutralization of IFN‐γ reduced liver damage in HBs‐Tg and HBs‐Tg‐TCR‐δ−/− mice to a similar extent. Further investigation revealed that HBs‐Tg mice showed an enhanced interleukin‐17 (IL‐17) signature. The administration of exogenous IL‐23 enhanced IL‐17A production from Vγ4 γδ T cells and ameliorated liver damage in HBs‐Tg mice, but not in HBs‐Tg‐TCR‐δ−/− mice. In summary, our results demonstrated that γδ T cells played a protective role in restraining Con A‐induced hepatitis by inhibiting IFN‐γ production from CD4+ T cells and are indispensable for IL‐23‐mediated protection against Con A‐induced hepatitis in HBs‐Tg mice. These results provided a potential therapeutic approach for treating the hypersensitivity of HBV carriers to biochemical stimulation‐induced liver damage. 相似文献