scholarly journals Immune response gene function correlates with the expression of an Ia antigen. II. A quantitative deficiency in A(e):E(a), complex expression causes a corresponding defect in antigen-presenting cell function

1982 ◽  
Vol 155 (2) ◽  
pp. 508-523 ◽  
Author(s):  
LA Matis ◽  
PP Jones ◽  
DB Murphy ◽  
SM Hedrick ◽  
EA Lerner ◽  
...  
Keyword(s):  
T Cell ◽  
Cytochrome C ◽  
Cell Surface ◽  
Proliferative Response ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Spleen Cells ◽  
Ia Antigen ◽  
Low Responder ◽  
Antigen Presenting

A series of experiments were performed to explore the role of complementing major histocompatability complex (MHC)-linked immune response Ir genes in the murine T cell proliferative response to the globular protein antigen pigeon cytochrome c. The functional equivalence of I-E-subregion-encoded, structurally homologous E(a) chains from different haplotypes bearing the serologic specificity Ia.7 was demonstrated by the complementation for high responsiveness to pigeon cytochrome c of F(1) hybrids between low responder B 10.A(4R) (I-A (k)) or B 10.S (I-A(8)) mice and four low responder E(a)- bearing haplotypes. Moreover, this Ir gene function correlated directly with both the ability of antigen-pulsed spleen cells from these same F(1) strains to stimulate pigeon cytochrome c-primed T cells from B10.A or B10.S(9R) mice, and with the cell surface expression of the two-chain Ia antigenic complex, A(e):E(a), bearing the conformational or combinatorial determinant recognized by the monoclonal anti-Ia antibody, Y-17. The B 10.PL strain (H-2(u)), which expresses an Ia.7-positive I-E- subregion-encoded E(a) chain, failed to complement with B10.A(4R) or B10.S mice in the response to pigeon cytochrome c. However, (B10.A(4R) × B10.PL)F(1) and (B10.S × B10.PL)F(1) mice do express A(k)(e):E(u)(a) and A(8)(e):E(u)(a) on their cell surface, although in reduced amounts relative to A(k,s)(e):E(k,d,p,r)(a) complexes found in corresponding F(1) strains. This quantitative difference in Ia antigen expression correlated with a difference in the ability to present pigeon cytochrome c to B 10.A and B 10.S(9R) long-term T cell lines. Thus, (B10.A(4R) × B10.PL)F(1) spleen cells required a 10-fold higher antigen dose to induce the same stimulation as (B10.A(4R) × B10.D2)F(1) spleen cells. In addition, the monoclonal antibody, Y-17, which reacts with A(e):E(a) molecules of several strains, had a greater inhibitory effect on the proliferative response to pigeon cytochrome c of B10.A T cells in the presence of (B10.A(4R) X B10.PL)F(1) spleen cells than in the presence of (B10.A(4R) X B10.D2)F(1) spleen cells. These functional data, in concert with the biochemical and serological data in the accompanying report, are consistent with the molecular model for Ir gene complementation in which appropriate two-chain Ia molecules function at the antigen-presenting cell (APC) surface as restriction elements. Moreover, they clearly demonstrate that the magnitude of the T cell proliferative response is a function of both the concentration of nominal antigen and of the amount of Ia antigen expressed on the APC. Finally, the direct correlation of a quantitative deficiency in cell surface expression of an Ia antigen with a corresponding relative defect in antigen-presenting function provides strong independent evidence that the I-region-encoded Ia antigens are the products of the MHC-linked Ir genes.

scholarly journals A Next Generation Bivalent Human Ad5 COVID-19 Vaccine Delivering Both Spike and Nucleocapsid Antigens Elicits Th1 Dominant CD4+, CD8+ T-cell and Neutralizing Antibody Responses

2020 ◽  
Author(s):  
Adrian Rice ◽  
Mohit Verma ◽  
Annie Shin ◽  
Lise Zakin ◽  
Peter Sieling ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Surface ◽  
Immune Responses ◽  
Cd8 T Cell ◽  
Surface Expression ◽  
Antibody Responses ◽  
Cell Surface Expression ◽  
Clinical Testing ◽  
Next Generation ◽  
Cell Responses

ABSTRACTIn response to the health crisis presented by the COVID-19 pandemic, rapid development of safe and effective vaccines that elicit durable immune responses is imperative. Recent reports have raised the concern that antibodies in COVID-19 convalescent patients may not be long lasting and thus even these individuals may require vaccination. Vaccine candidates currently in clinical testing have focused on the SARS-CoV-2 wild type spike (S) protein (S-WT) as the major antigen of choice and while pre-clinical and early clinical testing have shown that S elicits an antibody response, we believe the optimal vaccine candidate should be capable of inducing robust, durable T-cell responses as well as humoral responses. We report here on a next generation bivalent human adenovirus serotype 5 (hAd5) vaccine capable of inducing immunity in patients with pre-existing adenovirus immunity, comprising both an S sequence optimized for cell surface expression (S-Fusion) and a conserved nucleocapsid (N) antigen designed to be transported to the endosomal subcellular compartment, with the potential to generate durable immune protection. Our studies suggest that this bivalent vaccine is optimized for immunogenicity as evidenced by the following findings: (i) The optimized S-Fusion displayed improved S receptor binding domain (RBD) cell surface expression compared to S-WT where little surface expression was detected; (ii) the expressed RBD from S-Fusion retained conformational integrity and recognition by ACE2-Fc; (iii) the viral N protein modified with an enhanced T-cell stimulation domain (ETSD) localized to endosomal/lysosomal subcellular compartments for MHC I/II presentation; and (iv) these optimizations to S and N (S-Fusion and N-ETSD) generated enhanced de novo antigen-specific B cell and CD4+ and CD8+ T-cell responses in antigen-naive pre-clinical models. Both the T-cell and antibody immune responses to S and N demonstrated a T-helper 1 (Th1) bias. The antibody responses were neutralizing as demonstrated by two independent SARS-CoV-2 neutralization assays. Based on these findings, we are advancing this next generation bivalent hAd5 S-Fusion + N-ETSD vaccine as our lead clinical candidate to test for its ability to provide robust, durable cell-mediated and humoral immunity against SARS-CoV-2 infection. Further studies are ongoing to explore utilizing this vaccine construct in oral, intranasal, and sublingual formulations to induce mucosal immunity in addition to cell-mediated and humoral immunity. The ultimate goal of an ideal COVID-19 vaccine is to generate long-term T and B cell memory.

scholarly journals Antigen-specific T cell clones restricted to unique F(1) major histocompatibility complex determinants. Inhibition of proliferation with a monoclonal anti-Ia antibody

1981 ◽  
Vol 153 (3) ◽  
pp. 677-693 ◽  
Author(s):  
B Sredni ◽  
LA Matis ◽  
EA Lerner ◽  
WE Paul ◽  
RH Schwartz
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Proliferative Response ◽  
Cell Populations ◽  
Gene Products ◽  
Spleen Cells ◽  
Histocompatibility Complex ◽  
Cell Clones ◽  
Antigen Presenting

The existence of T cells specific for soluble antigens in association with unique F(1) or recombinant major histocompatibility complex (MHC) gene products was first postulated from studies on the proliferative response of whole T cell populations to the antigen poly(Glu(55)Lys(36)Phe(9))(n) (GLφ). In this paper we use the newly developed technology of T lymphocyte cloning to establish unequivocally the existence of such cells specific for GLφ and to generalize their existence by showing that F(1)- specific cells can be isolated from T cell populations primed to poly(Glu(60)Ala(30)Tyr(10))(n) (GAT) where such clones represent only a minor subpopulation of cells. Gl.4b-primed B10.A(5R) and GAT-primed (B10.A × B10)F(1) lymph node T cells were cloned in soft agar, and the colonies that developed were picked and expanded in liquid culture. The GLφ-specific T cells were then recloned under conditions of high-plating efficiency to ensure that the final colonies originated from single cells. T cells from such rigorously cloned populations responded to stimulation with GILφ but only in the presence of nonimmune, irradiated spleen cells bearing (B10.A × B10)F(1) or the syngeneic B 10.A(5R) recombinant MHC haplotype. Spleen cells from either the B10 or B 10.A parental strains failed to support a proliferative response, even when added together. (B10 × B10.D2)F(1) and (B10 × B10.RIII)F(1) spleen cells also supported a proliferative response but (B10 × B10.Q)F(1) and (B10 X B10.S)F(1) spleen cells did not. These results suggested that the T cell clones were specific for GL[phi} in association with the β(AE)(b)-α(E) (k,d,r,) Ia molecule and that recognition required both gene products to be expressed in the same antigen-presenting cells. Support for this interpretation was obtained from inhibition experiments using the monoclonal antibody Y-17 specific for a determinant on the β(AE)(b)-αE Ia molecule. Y-17 completely inhibited the proliferative response of a GLφ-specific clone but had no effect on the response of either a PPD-specific or GAT-specific clone, both of which required the β(A)-α(A) Ia molecule as their restriction element. No evidence could be found for the involvement of suppressor T cells in this inhibition. We therefore conclude that the phenomenon of F(1)-restricted recognition by proliferating T cells results from the presence of antigen- specific clones that must recognize unique F(1) or recombinant Ia molecules on the surface of antigen-presenting cells in addition to antigen in order to be stimulated.

Protein Phosphatase 2A Isotypes Regulate Cell Surface Expression of the T Cell Receptor

2001 ◽  
Vol 18 (1) ◽  
pp. 24-33 ◽  
Author(s):  
Jens Peter H. Lauritsen ◽  
Charlotte Menné ◽  
Jesper Kastrup ◽  
Jes Dietrich ◽  
Carsten Geisler
Keyword(s):  
T Cell ◽  
Cell Surface ◽  
T Cell Receptor ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Cell Receptor ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Phosphatase 2A

Identification of a T cell lineage-specific RNA/DNA helicase and its cell surface expression during intrathymic education of αβ and γδ T cells

1997 ◽  
Vol 27 (12) ◽  
pp. 3269-3282 ◽  
Author(s):  
Arkadiusz Miazek ◽  
Manfred Brockhaus ◽  
Hanno Langen ◽  
Andrea Braun ◽  
Pawel Kisielow
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Cell Lineage ◽  
Γδ T Cells ◽  
Surface Expression ◽  
Dna Helicase ◽  
Cell Surface Expression

scholarly journals Varicella-Zoster Virus Productively Infects Mature Dendritic Cells and Alters Their Immune Function

2003 ◽  
Vol 77 (8) ◽  
pp. 4950-4959 ◽  
Author(s):  
Gavin Morrow ◽  
Barry Slobedman ◽  
Anthony L. Cunningham ◽  
Allison Abendroth
Keyword(s):  
Dendritic Cells ◽  
Cell Surface ◽  
Mhc Class Ii ◽  
Surface Expression ◽  
Immunofluorescent Staining ◽  
Cell Surface Expression ◽  
Varicella Zoster ◽  
Cytoplasmic Vesicles ◽  
Antigen Presenting ◽  
Replicative Cycle

ABSTRACT Mature dendritic cells (DCs) are potent antigen-presenting cells essential for initiating successful antiviral immune responses and would therefore serve as an ideal target for viruses seeking to evade or delay the immune response by disrupting their function. We have previously reported that VZV productively infects immature DCs (A. Abendroth, G. Morrow, A. L. Cunningham, and B. Slobedman, J. Virol. 75:6183-6192, 2001), and in the present study we assessed the ability of VZV to infect mature DCs. Mature DCs were generated from immature monocyte-derived DCs by lipopolysaccharide treatment before being exposed to VZV-infected fibroblasts. On day 4 postexposure, flow cytometry analysis revealed that 15 to 45% of mature DCs were VZV antigen positive, and immunofluorescent staining together with infectious-center assays demonstrated that these cells were fully permissive for the complete VZV replicative cycle. VZV infection of mature DCs resulted in a selective downregulation of cell surface expression of the functionally important immune molecules major histocompatibility complex (MHC) class I, CD80, CD83, and CD86 but did not alter MHC class II expression. Immunofluorescent staining showed that the downregulation of cell surface CD83 was concomitant with a retention of CD83 in cytoplasmic vesicles. Importantly, VZV infection of mature DCs significantly reduced their ability to stimulate the proliferation of allogeneic T lymphocytes. These data demonstrate that mature DCs are permissive for VZV and that infection of these cells reduces their ability to function properly. Thus, VZV has evolved yet another immune evasion strategy that would likely impair immunosurveillance and enhance the chances for lifelong persistence in the human population.

scholarly journals Interleukin 2 upregulates expression of its receptor on a T cell clone.

1985 ◽  
Vol 161 (6) ◽  
pp. 1575-1580 ◽  
Author(s):  
T R Malek ◽  
J D Ashwell
Keyword(s):  
T Cell ◽  
Cell Surface ◽  
Messenger Rna ◽  
Cell Clone ◽  
Interleukin 2 ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Initial Acquisition ◽  
T Cell Clone ◽  
Stimulation Of

Stimulation of a class II-restricted, antigen-specific T cell clone with interleukin 2 (IL-2) resulted in substantial increases in both cell surface IL-2 receptor (IL-2-R) and cytoplasmic IL-2-R messenger RNA (mRNA), whereas no increase was observed for cell-surface expression of Thy-1 and L3T4 antigens, and only a modest increase in Thy-1 mRNA was observed. These experiments demonstrate that, after initial acquisition of the IL-2-R, IL-2 as well as antigen is able to directly upregulate both the level of IL-2-R mRNA and cell surface IL-2-R molecules.

scholarly journals Unstable B7-H4 cell surface expression and T-cell redirection as a means of cancer therapy

2016 ◽  
Vol 36 (5) ◽  
pp. 2625-2632
Author(s):  
Akira Iizuka ◽  
Ryota Kondou ◽  
Chizu Nonomura ◽  
Tadashi Ashizawa ◽  
Keiichi Ohshima ◽  
...  
Keyword(s):  
T Cell ◽  
Cancer Therapy ◽  
Cell Surface ◽  
Surface Expression ◽  
Cell Surface Expression
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