Dominant T-cell recognition of sepcific epitopes of PP65 in the immune response against HCMV

Following the advent of immunotherapy as a possible cure for cancer, remarkable insight has been gained on the role of mutational load and neoantigens as key ingredients in T cell recognition of malignancies. However, not all highly mutational tumors react to immune therapies, and even initial success is often followed by eventual relapse. Recent research points out that high heterogeneity in the neoantigen landscape of a tumor might be key in understanding the failure of immune surveillance. In this work we present a mathematical framework able to describe how neoantigen distributions shape the immune response. Modeling T cell reactivity as a function of antigen dominancy and distribution across a tumor indicates the existence of a diversity threshold beyond which T cells fail at controling heterogeneous cancer growth. Furthemore, an analytical estimate for the evolution of average antigen clonality indicates rapid increases in epitope heterogeneity in early malignancy growth. In this scenario, we propose that therapies targeting the tumor prior to immunotherapy can reduce neoantigen heterogeneity, and postulate the existence of a time window, before tumor relapse due to de novo resistance, rendering immunotherapy more effective.Major FindingsGenetic heterogeneity affects the immune response to an evolving tumor by shaping the neoantigen landscape of the cancer cells, and highly heterogeneous tumors seem to escape T cell recognition. Mathematical modeling predicts the existence of a well defined neoantigen diversity threshold, beyond which lymphocites are not able to counteract the growth of a population of highly heterogeneous subclones. Furthermore, evolutionary dynamics predict a fast decay of neoantigen clonality, rendering advanced tumors hard to attack at the time of immunotherapy. Within this mathematical framework we propose that targeted therapy forcing a selective pressure for resistance might as well increase neoantigen homogeneity, providing a novel possibility for combination therapy.

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Inhibition of T cell and antibody responses to house dust mite allergen by inhalation of the dominant T cell epitope in naive and sensitized mice.

Journal of Experimental Medicine ◽

10.1084/jem.178.5.1783 ◽

1993 ◽

Vol 178 (5) ◽

pp. 1783-1788 ◽

Cited By ~ 246

Author(s):

G F Hoyne ◽

R E O'Hehir ◽

D C Wraith ◽

W R Thomas ◽

J R Lamb

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Cell Epitope ◽

Cell Recognition ◽

T Cell Epitope ◽

T Cell Recognition ◽

Dust Mite ◽

Der P 1

Antigen-specific CD4+ T cells play an important role in the allergic immune response to house dust mite (HDM) allergens in humans. The group 1 allergen of Dermatophagoides spp. is a major target antigen in both B and T cell recognition of HDM. In vitro studies have shown that the presentation of peptides to human T cells under appropriate conditions may lead to a state of specific nonresponsiveness. Therefore, to determine if peptides are able to modulate the function of allergen-reactive T cells in vivo, we have used a murine model of T cell recognition of the HDM allergen Der p 1. The results demonstrate that inhalation of low concentrations of peptide containing the major T cell epitope of Der p 1 (residues 111-139), induces tolerance in naive C57BL/6J mice such that they become profoundly unresponsive to an immunogenic challenge with the intact allergen. When restimulated in vitro with antigen, lymph node T cells isolated from tolerant mice secrete very low levels of interleukin 2, proliferative poorly, and are unable to provide cognate help to stimulate specific antibody production. Furthermore, intranasal peptide therapy was able to inhibit an ongoing immune response to the allergen in mice and this has potential implications in the development of allergen-based immunotherapy.

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Effect of Costimulation and the Microenvironment on Antigen Presentation by Leukemic Cells

Blood ◽

10.1182/blood.v94.10.3479.422k29_3479_3490 ◽

1999 ◽

Vol 94 (10) ◽

pp. 3479-3490 ◽

Cited By ~ 41

Author(s):

A.G.S. Buggins ◽

N. Lea ◽

J. Gäken ◽

D. Darling ◽

F. Farzaneh ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Tumor Cells ◽

Costimulatory Molecule ◽

Leukemic Cells ◽

Cell Mediated Immunity ◽

Cell Recognition ◽

T Cell Recognition ◽

Th1 Cytokines

Costimulatory signals supplied by genetically modified tumor cells can enable T-cell recognition of tumor-associated antigens that were previously silent when presented by unmodified tumor cells. Although the mechanism of the CD80/CD28 costimulation has been studied extensively in the normal T-cell/antigen-presenting cell (APC) interactions, it is unclear how expression of CD80 by tumor cells mediates its effect. We demonstrate here that optimal CD80 expression on a leukemic cell enhances T-cell recognition of alloantigen primarily by lowering the level of T-cell receptor (TCR) stimulation required for activation. CD80 expression by leukemic cells leads to increased survival of activated T cells by inducing upregulation of the antiapoptotic protein BCL-2, but not BCL-XL. The cytokine microenvironment in which T cells are activated is crucial in determining their differentiation and consequently the nature of the immune response generated. Many tumor cells produce immunosuppressive cytokines that may not favor the induction of cell-mediated immunity. In this study, the presence of CD80 on leukemic cells increased T-cell activation in vitro, but this did not result in the production of Th1 cytokines. We show that this is due to a leukemia-derived soluble factor that inhibits the production of Th1 cytokines. Optimal expression of a costimulatory molecule, therefore, enhances the ability of leukemic cells to present antigen by amplifying TCR signals, but the microenvironment generated by leukemic cells may suppress the immune response required for their eradication. Thus, strategies aimed at inducing antileukemic immunity by providing leukemic cells with costimulatory functions must ensure the presence of an appropriate microenvironment.

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The Major Histocompatibility Complex Haplotype Affects T-Cell Recognition of Mycobacterial Antigens but Not Resistance to Mycobacterium tuberculosis in C3H Mice

Infection and Immunity ◽

10.1128/iai.72.12.6790-6798.2004 ◽

2004 ◽

Vol 72 (12) ◽

pp. 6790-6798 ◽

Cited By ~ 29

Author(s):

Arati B. Kamath ◽

Jennifer Alt ◽

Hajer Debbabi ◽

Chad Taylor ◽

Samuel M. Behar

Keyword(s):

Immune Response ◽

T Cell ◽

Cell Recognition ◽

T Cell Recognition ◽

Histocompatibility Complex ◽

C3h Mice ◽

Mhc Haplotype ◽

Ifn Γ ◽

Mhc Locus ◽

Mycobacterial Antigens

ABSTRACT Both innate and adaptive immunity play an important role in host resistance to Mycobacterium tuberculosis infection. Although several studies have suggested that the major histocompatibility complex (MHC) haplotype affects susceptibility to infection, it remains unclear whether the modulation of T-cell immunity by the MHC locus determines the host's susceptibility to tuberculosis. To determine whether allelic differences in the MHC locus affect the T-cell immune response after M. tuberculosis infection, we infected inbred and H-2 congenic mouse strains by the respiratory route. The H-2 locus has a profound effect on the antigen-specific CD4+-T-cell response after M. tuberculosis infection. CD4+ T cells from infected mice of the H-2b haplotype produced more gamma interferon (IFN-γ) after in vitro stimulation with mycobacterial antigens than mice of the H-2k haplotype. A higher level of IFN-γ was also detected in bronchoalveolar lavage fluid from infected mice of the H-2b haplotype. Furthermore, C3.SW-H2b/SnJ mice generate and recruit activated T cells to the lung after infection. Despite a robust immune response, C3.SW-H2b/SnJ mice succumbed to infection early and were similarly susceptible to infection as other C3H (H-2k) substrains. These results suggest that although the MHC haplotype has a profound impact on the T-cell recognition of M. tuberculosis antigens, the susceptibility of C3H mice to infection is MHC independent.

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ANTIGEN MAPPING FOR T CELL RECOGNITION: IMMUNE RESPONSE GENE CONTROL OF DETERMINANT SELECTION

Regulatory Mechanisms in Lymphocyte Activation ◽

10.1016/b978-0-12-458050-3.50044-8 ◽

1977 ◽

pp. 382-384

Author(s):

Marcello A. Barcinski ◽

Alan S. Rosenthal

Keyword(s):

Immune Response ◽

T Cell ◽

Immune Response Gene ◽

Gene Control ◽

Cell Recognition ◽

Response Gene ◽

T Cell Recognition

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Faculty Opinions recommendation of The human prion protein residue 129 polymorphism lies within a cluster of epitopes for T cell recognition.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1052901.504839 ◽

2006 ◽

Author(s):

Alejandro Schaffer

Keyword(s):

T Cell ◽

Prion Protein ◽

Cell Recognition ◽

T Cell Recognition ◽

Human Prion Protein

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Topoisomerase inhibitors modulate expression of melanocytic antigens and enhance T cell recognition of tumor cells

Cancer Immunology Immunotherapy ◽

10.1007/s00262-010-0926-x ◽

2010 ◽

Vol 60 (1) ◽

pp. 133-144 ◽

Cited By ~ 17

Author(s):

Timothy J. Haggerty ◽

Ian S. Dunn ◽

Lenora B. Rose ◽

Estelle E. Newton ◽

Sunil Martin ◽

...

Keyword(s):

T Cell ◽

Tumor Cells ◽

Cell Recognition ◽

Topoisomerase Inhibitors ◽

T Cell Recognition

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Cell-mediated lympholysis to H-2-matched target cells modified with a series of nitrophenyl compounds.

Journal of Experimental Medicine ◽

10.1084/jem.144.4.1134 ◽

1976 ◽

Vol 144 (4) ◽

pp. 1134-1140 ◽

Cited By ~ 24

Author(s):

T G Rehn ◽

J K Inman ◽

G M Shearer

Keyword(s):

T Cell ◽

Target Cells ◽

Cell Recognition ◽

Receptor Model ◽

Spleen Cells ◽

Effector Cells ◽

T Cell Recognition ◽

Cytotoxic Effector

The specificity of C57BL/10 cytotoxic effector cells generated by in vitro sensitization with autologous spleen cells modified with a series of related nitrophenyl compounds was investigated. The failure of trinitrophenyl (TNP)-sensitized effector cells to lyse TNP-beta-alanylglycylglycyl(AGG)-modified target cells is presented as evidence contradicting the intimacy or dual receptor model or T-cell recognition in its simplest form. Data are also shown indicating that sensitization with N-(3-nitro-4-hydroxy-5-iodophenylacetyl)-AGG-modified stimulating cells generates noncross-reacting clones of cytotoxic effector cells.

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