scholarly journals Self major histocompatibility complex class I antigens expressed solely in lymphoid cells do not induce tolerance in the CD4+ T cell compartment.

1996 ◽  
Vol 184 (4) ◽  
pp. 1573-1578 ◽  
Author(s):  
R Schulz ◽  
A L Mellor
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Lymphoid Cells ◽  
Cd4 T Cell ◽  
Cell Compartment ◽  
Mhc I ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Self Peptides

Transgenic mice expressing self major histocompatibility complex (MHC) class I (H-2Kb) antigen solely in lymphoid cell lineages do not acquire tolerance to H-2Kb expressed on skin grafts. H-2Kb-specific cytotoxic T cell responses were completely abrogated in these mice, even after they had rejected skin grafts. Moreover, thymocytes expressing T cell receptors that confer H-2Kb reactivity on cytotoxic CD8+ T cells were eliminated. The ability to reject grafts correlated with the presence of a novel population of H-2Kb-reactive CD4+ T cells. At least some of these CD4+ T cells recognize peptides derived from H-2Kb by processing. We conclude that self MHC I antigens induce tolerance in the CD8 T cell compartment via negative selection when expressed exclusively by lymphoid cells. In contrast, tolerance to MHC class II-restricted self peptides derived by processing of such MHC I antigens is not induced in the CD4 T cell compartment. This suggests that effective transfer of self antigens from lymphoid cells to MHC II-positive cells that can process and present them as self peptides to thymocytes or CD4+ T cells does not take place in vivo. Thus, sequestration of self antigens and MHC II molecules in distinct cell types in the thymic microenvironment allows potentially autoreactive and functionally competent CD4+ T cells that recognize cryptic MHC II-restricted self peptides to mature into the peripheral T cell repertoire under normal physiological circumstances.

scholarly journals The critical role of CD4+ T cells in PD-1 blockade against MHC-II–expressing tumors such as classic Hodgkin lymphoma

2020 ◽  
Vol 4 (17) ◽  
pp. 4069-4082
Author(s):  
Joji Nagasaki ◽  
Yosuke Togashi ◽  
Takeaki Sugawara ◽  
Makiko Itami ◽  
Nobuhiko Yamauchi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Critical Role ◽  
Cd4 T Cell ◽  
Antitumor Effects ◽  
Cell Axis ◽  
Mhc I ◽  
Mhc Ii

Abstract Classic Hodgkin lymphoma (cHL) responds markedly to PD-1 blockade therapy, and the clinical responses are reportedly dependent on expression of major histocompatibility complex class II (MHC-II). This dependence is different from other solid tumors, in which the MHC class I (MHC-I)/CD8+ T-cell axis plays a critical role. In this study, we investigated the role of the MHC-II/CD4+ T-cell axis in the antitumor effect of PD-1 blockade on cHL. In cHL, MHC-I expression was frequently lost, but MHC-II expression was maintained. CD4+ T cells highly infiltrated the tumor microenvironment of MHC-II–expressing cHL, regardless of MHC-I expression status. Consequently, CD4+ T-cell, but not CD8+ T-cell, infiltration was a good prognostic factor in cHL, and PD-1 blockade showed antitumor efficacy against MHC-II–expressing cHL associated with CD4+ T-cell infiltration. Murine lymphoma and solid tumor models revealed the critical role of antitumor effects mediated by CD4+ T cells: an anti-PD-1 monoclonal antibody exerted antitumor effects on MHC-I−MHC-II+ tumors but not on MHC-I−MHC-II− tumors, in a cytotoxic CD4+ T-cell–dependent manner. Furthermore, LAG-3, which reportedly binds to MHC-II, was highly expressed by tumor-infiltrating CD4+ T cells in MHC-II–expressing tumors. Therefore, the combination of LAG-3 blockade with PD-1 blockade showed a far stronger antitumor immunity compared with either treatment alone. We propose that PD-1 blockade therapies have antitumor effects on MHC-II–expressing tumors such as cHL that are mediated by cytotoxic CD4+ T cells and that LAG-3 could be a candidate for combination therapy with PD-1 blockade.

scholarly journals Cytomegalovirus-Specific CD4 T Cells Are Cytolytic and Mediate Vaccine Protection

2015 ◽  
Vol 90 (2) ◽  
pp. 650-658 ◽  
Author(s):  
Shilpi Verma ◽  
Daniela Weiskopf ◽  
Ankan Gupta ◽  
Bryan McDonald ◽  
Bjoern Peters ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Major Histocompatibility Complex Class ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Complex Class ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Class Ii Mhc

ABSTRACTCD4 T cells provide protection against cytomegalovirus (CMV) and other persistent viruses, and the ability to quantify and characterize epitope-specific responses is essential to gain a more precise understanding of their effector roles in this regard. Here, we report the first two I-Ad-restricted CD4 T cell responses specific for mouse CMV (MCMV) epitopes and use a major histocompatibility complex class II (MHC-II) tetramer to characterize their phenotypes and functions. We demonstrate that MCMV-specific CD4 T cells can express high levels of granzyme B and kill target cells in an epitope- and organ-specific manner. In addition, CD4 T cell epitope vaccination of immunocompetent mice reduced MCMV replication in the same organs where CD4 cytotoxic T lymphocyte (CTL) activity was observed. Together, our studies show that MCMV epitope-specific CD4 T cells have the potential to mediate antiviral defense by multiple effector mechanismsin vivo.IMPORTANCECD4 T cells mediate immune protection by using their T cell receptors to recognize specific portions of viral proteins, called epitopes, that are presented by major histocompatibility complex class II (MHC-II) molecules on the surfaces of professional antigen-presenting cells (APCs). In this study, we discovered the first two epitopes derived from mouse cytomegalovirus (MCMV) that are recognized by CD4 T cells in BALB/c mice, a mouse strain commonly used to study the pathogenesis of this virus infection. Here, we report the sequences of these epitopes, characterize the CD4 T cells that recognize them to fight off MCMV infection, and show that we can use the epitopes to vaccinate mice and protect against MCMV.

scholarly journals CD4 T Cells and Major Histocompatibility Complex Class II Expression Influence Worm Expulsion and Increased Intestinal Muscle Contraction during Trichinella spiralisInfection

1999 ◽  
Vol 67 (11) ◽  
pp. 6090-6097 ◽  
Author(s):  
Bruce A. Vallance ◽  
Francesca Galeazzi ◽  
Stephen M. Collins ◽  
Denis P. Snider
Keyword(s):  
T Cells ◽  
T Cell ◽  
Muscle Contraction ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Worm Expulsion ◽  
Deficient Mice

ABSTRACT Expulsion of intestinal nematode parasites and the associated increased contraction by intestinal muscle are T cell dependent, since both are attenuated in athymic rodents. The CD4 T-cell subset has been strongly associated with worm expulsion; however, the relationship between these cells, antigen presentation, and worm expulsion is not definitive and the role of these factors in intestinal muscle hypercontractility has not been defined. We infected C57BL/6, athymic, CD4-deficient, CD8α-deficient, and major histocompatibility complex class II (MHC II)-deficient (C2d) mice with Trichinella spiralis larvae. We examined intestinal worm numbers, longitudinal muscle contraction, and MHC II expression. Numerous MHC II-positive cells were identified within the muscularis externa of infected but not uninfected C57BL/6 mice. C57BL/6 and CD8α-deficient mice developed large increases in muscle contraction, expelling the parasite by day 21. Athymic and C2d mice exhibited much smaller increases in muscle contraction and delayed parasite expulsion. CD4-deficient mice exhibited intermediate levels of muscle contraction and delayed parasite expulsion. To further examine the role of MHC II and CD4 T cells, we irradiated C2d mice and reconstituted them with C57BL/6 bone marrow alone or with C57BL/6 CD4 T cells. C57BL/6 bone marrow alone did not affect muscle function or worm expulsion in recipient C2d mice. Partial CD4 T-cell reconstitution was sufficient to restore increased muscle contraction but not worm expulsion. Thus, hematopoietic MHC II expression alone is insufficient for the development of muscle hypercontractility and worm expulsion, but the addition of even small numbers of CD4 T cells was sufficient to induce intestinal muscle pathophysiology.

scholarly journals Telomerase and CD4 T Cell Immunity in Cancer

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1687
Author(s):  
Magalie Dosset ◽  
Andrea Castro ◽  
Hannah Carter ◽  
Maurizio Zanetti
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Critical Role ◽  
Tumor Formation ◽  
T Cell Immunity ◽  
Cd4 T Cell ◽  
Current Status ◽  
Mhc Ii ◽  
Cell Immunity

Telomerase reverse transcriptase (TERT) is a conserved self-tumor antigen which is overexpressed in most tumors and plays a critical role in tumor formation and progression. As such, TERT is an antigen of great relevance to develop widely applicable immunotherapies. CD4 T cells play a major role in the anti-cancer response alone or with other effector cells such as CD8 T cells and NK cells. To date, efforts have been made to identify TERT peptides capable of stimulating CD4 T cells that are also able to bind diverse MHC-II alleles to ease immune status monitoring and immunotherapies. Here, we review the current status of TERT biology, TERT/MHC-II immunobiology, and past and current vaccine clinical trials. We propose that monitoring CD4 T cell immunity against TERT is a simple and direct way to assess immune surveillance in cancer patients and a new way to predict the response to immune checkpoint inhibitors (ICPi). Finally, we present the initial results of a systematic discovery of TERT peptides able to bind the most common HLA Class II alleles worldwide and show that the repertoire of MHC-II TERT peptides is wider than currently appreciated.

scholarly journals Second Class Minors

2003 ◽  
Vol 197 (3) ◽  
pp. 375-385 ◽  
Author(s):  
Hiroeki Sahara ◽  
Nilabh Shastri
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Interleukin 4 ◽  
General Strategy ◽  
Mhc Ii ◽  
Cell Responses ◽  
Antigen Presenting

CD4 T cells regulate immune responses that cause chronic graft rejection and graft versus host disease but their target antigens remain virtually unknown. We developed a new method to identify CD4 T cell–stimulating antigens. LacZ-inducible CD4 T cells were used as a probe to detect their cognate peptide/MHC II ligand generated in dendritic cells fed with Escherichia coli expressing a library of target cell genes. The murine H46 locus on chromosome 7 was thus found to encode the interleukin 4–induced IL4i1 gene. The IL4i1 precursor contains the HAFVEAIPELQGHV peptide which is presented by Ab major histocompatibility complex class II molecule via an endogenous pathway in professional antigen presenting cells. Both allelic peptides bind Ab and a single alanine to methionine substitution at p2 defines nonself. These results reveal novel features of H loci that regulate CD4 T cell responses as well as provide a general strategy for identifying elusive antigens that elicit CD4 T cell responses to tumors or self-tissues in autoimmunity.

scholarly journals Self-recognition drives the preferential accumulation of promiscuous CD4+ T-cells in aged mice

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Neha R Deshpande ◽  
Heather L Parrish ◽  
Michael S Kuhns
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cell Biology ◽  
Fold Increase ◽  
Cell Receptor ◽  
Cd4 T Cell ◽  
Fundamental Aspect ◽  
Cell Compartment ◽  
Old Mice

T-cell recognition of self and foreign peptide antigens presented in major histocompatibility complex molecules (pMHC) is essential for life-long immunity. How the ability of the CD4+ T-cell compartment to bind self- and foreign-pMHC changes over the lifespan remains a fundamental aspect of T-cell biology that is largely unexplored. We report that, while old mice (18–22 months) contain fewer CD4+ T-cells compared with adults (8–12 weeks), those that remain have a higher intrinsic affinity for self-pMHC, as measured by CD5 expression. Old mice also have more cells that bind individual or multiple distinct foreign-pMHCs, and the fold increase in pMHC-binding populations is directly related to their CD5 levels. These data demonstrate that the CD4+ T-cell compartment preferentially accumulates promiscuous constituents with age as a consequence of higher affinity T-cell receptor interactions with self-pMHC.

Age-Related Induction of CD4+ T-Cell Unresponsiveness Is Reversible and Dependant of the Host’s Environment.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3925-3925
Author(s):  
Pedro Horna ◽  
Rahul Chavan ◽  
Jason Brayer ◽  
Ildefonso Suarez ◽  
Eduardo M. Sotomayor
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Cell Compartment ◽  
Memory Phenotype ◽  
Age Related ◽  
And Function

Abstract A large number of CD4+ T-cells from either aged mice or humans display surface markers associated with an activated/memory phenotype. In spite of these changes however, these T-cells have a markedly decreased ability to proliferate and produce IL-2 in response to antigen stimulation in vitro. The cellular and molecular mechanisms involved in this age-related unresponsiveness of the CD4+ T-cell compartment remain poorly understood. Utilizing a well-established experimental system in which transgenic CD4+ T cells specific for a MHC class II restricted epitope of influenza hemagglutinin (HA) are adoptively transferred into non-transgenic recipients, we have previously elucidated important mechanisms involved in the induction and maintenance of CD4+ T-cell tolerance. Our studies were however limited to the analysis of T-cell function in lymphoma bearing young mice (4 to 10 weeks old). Here, we assessed the influence of the aged microenvironment in determining the phenotype and function of antigen-specific T-cells. CD4+ T-cells from young TCR transgenic mice (2 months old) were adoptively transferred into either old (20–24 months) or young (2 months old) non-transgenic mice. Two weeks later, clonotypic and non-clonotypic CD4+ T-cells were isolated from the spleens of these animals and their phenotype and function were determined in vitro. Reminiscent of the age-related changes observed within the normal CD4+ T-cell repertoire, young transgenic T-cells transferred into aged hosts have acquired an activated/memory phenotype but displayed a significant impairment in antigen-specific proliferation and IL-2 production in response to cognate antigen in vitro. These changes were not due to homeostatic proliferation of the transferred T-cells into the relatively lymphopenic aged host. To determine whether the changes observed in “aged” T-cells were reversible or not, we adoptively transfer old T-cells back into young hosts or into control old mice. While old transgenic T-cells transferred into an old environment remained fully unresponsive, the adoptive transfer of the same old T-cells into a young host restored their ability to proliferate and produce IL-2. Surprisingly, these “old” T-cells were able to produce significantly higher levels of IFN-gamma indicative of their memory/effector phenotype. Furthermore, young animals adoptively transferred with “aged” antigen-specific T-cells were now capable of rejecting A20 B-cell lymphomas expressing HA as a model tumor antigen (A20HA). Taking together, factor(s) present in the aged microenvironment are responsible for limiting the effector function of CD4+ T-cells that seem otherwise well equipped to become fully activated if the proper environment is provided (young microenvironment). The potential role of soluble suppressive factors as well as regulatory T-cells (Tregs) in the unresponsiveness observed in the T-cell compartment of aged hosts will be discussed.

scholarly journals Dynamic balance between master transcription factors determines the fates and functions of CD4 T cell and innate lymphoid cell subsets

2017 ◽  
Vol 214 (7) ◽  
pp. 1861-1876 ◽  
Author(s):  
Difeng Fang ◽  
Jinfang Zhu
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
T Cell ◽  
Cd4 T Cells ◽  
T Regulatory Cells ◽  
Dynamic Balance ◽  
Treg Cells ◽  
Lymphoid Cells ◽  
Cd4 T Cell ◽  
Master Regulators

CD4 T cells, including T regulatory cells (Treg cells) and effector T helper cells (Th cells), and recently identified innate lymphoid cells (ILCs) play important roles in host defense and inflammation. Both CD4 T cells and ILCs can be classified into distinct lineages based on their functions and the expression of lineage-specific genes, including those encoding effector cytokines, cell surface markers, and key transcription factors. It was first recognized that each lineage expresses a specific master transcription factor and the expression of these factors is mutually exclusive because of cross-regulation among these factors. However, recent studies indicate that the master regulators are often coexpressed. Furthermore, the expression of master regulators can be dynamic and quantitative. In this review, we will first discuss similarities and differences between the development and functions of CD4 T cell and ILC subsets and then summarize recent literature on quantitative, dynamic, and cell type–specific balance between the master transcription factors in determining heterogeneity and plasticity of these subsets.

scholarly journals Regulatory CD4 T Cells Control the Size of the Peripheral Activated/Memory CD4 T Cell Compartment

2000 ◽  
Vol 164 (7) ◽  
pp. 3573-3580 ◽  
Author(s):  
Oliver Annacker ◽  
Odile Burlen-Defranoux ◽  
Ricardo Pimenta-Araujo ◽  
Ana Cumano ◽  
Antonio Bandeira
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Cell Compartment

scholarly journals MHC Class II Expression Restricted to CD8α+ and CD11b+ Dendritic Cells Is Sufficient for Control of Leishmania major

2004 ◽  
Vol 199 (5) ◽  
pp. 725-730 ◽  
Author(s):  
Maria P. Lemos ◽  
Fatima Esquivel ◽  
Phillip Scott ◽  
Terri M. Laufer
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
Cd4 T Cells ◽  
Leishmania Major ◽  
Cd4 T Cell ◽  
Major Infection ◽  
Mhc Ii ◽  
Antigen Presenting

Control of the intracellular protozoan, Leishmania major, requires major histocompatibility complex class II (MHC II)–dependent antigen presentation and CD4+ T cell T helper cell 1 (Th1) differentiation. MHC II–positive macrophages are a primary target of infection and a crucial effector cell controlling parasite growth, yet their function as antigen-presenting cells remains controversial. Similarly, infected Langerhans cells (LCs) can prime interferon (IFN)γ–producing Th1 CD4+ T cells, but whether they are required for Th1 responses is unknown. We explored the antigen-presenting cell requirement during primary L. major infection using a mouse model in which MHC II, I-Aβb, expression is restricted to CD11b+ and CD8α+ dendritic cells (DCs). Importantly, B cells, macrophages, and LCs are all MHC II–negative in these mice. We demonstrate that antigen presentation by these DC subsets is sufficient to control a subcutaneous L. major infection. CD4+ T cells undergo complete Th1 differentiation with parasite-specific secretion of IFNγ. Macrophages produce inducible nitric oxide synthase, accumulate at infected sites, and control parasite numbers in the absence of MHC II expression. Therefore, CD11b+ and CD8α+ DCs are not only key initiators of the primary response but also provide all the necessary cognate interactions for CD4+ T cell Th1 effectors to control this protozoan infection.

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