Generation of human tumor-reactive cytotoxic T cells against peptides presented by non-self HLA class I molecules

Abstract Soluble anti-HLA class I monoclonal antibodies (MoAbs) modulate normal T-lymphocyte proliferation induced via the CD3/Ti and the CD2 pathway, but do not induce proliferation of normal T lymphocytes in the absence of additional mitogenic stimuli. In this report, we show that anti-HLA class I MoAbs induce DNA synthesis in peripheral blood mononuclear cells from a patient with a CD4+CD8+T-prolymphocytic leukemia (T-PLL) and from a patient with a CD4-CD8+ T-chronic lymphocytic leukemia (T- CLL), in the absence of detectable additional mitogenic stimuli. Proliferation of leukemic T cells is induced by both whole Igs and Fab' fragments of anti-HLA class I MoAbs, arguing in favor of their direct interactions with the proliferating cells as the mechanism underlying the mitogenic effect. This interpretation is also supported by the ability of anti-HLA class I MoAbs to induce proliferation of leukemic T- cell preparations, depleted of accessory cells. DNA synthesis in T-CLL and T-PLL cells is preceded by expression of G1-specific messenger RNAs, ie. c-myc, 2F1, Tac, and interferon-gamma, in activated cells. Cell proliferation is inhibited by the protein kinase C inhibitor H7, indicating that activation of this enzyme is required for the mitogenic effect of anti-HLA class I MoAbs. The latter inhibit the proliferation of T-CLL cells as well as that of normal T cells stimulated with anti- CD3 MoAbs and enhance that of both types of cells stimulated with anti- CD2 MoAbs. In addition, anti-HLA class I MoAb Q6/64 in combination with anti-CD2 MoAb 9.6 or MoAb 9–1 induces proliferation of leukemic T cells to a greater extent than the individual MoAbs, but is not mitogenic for normal T cells. Anti-HLA class I MoAbs restore the cytolytic activity of T-CLL cells that is lost after 5 days of incubation of control medium, suggesting that HLA class I antigens may mediate a signal contributing to the activation state. The present results indicate that leukemic T-cell proliferation can be triggered via HLA class I molecules and suggest a potential role for these antigens in the in vivo growth of malignant clones.

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Fas-Independent Apoptosis of Activated T Cells Induced by Antibodies to the HLA Class I α1 Domain

Blood ◽

10.1182/blood.v90.9.3629 ◽

1997 ◽

Vol 90 (9) ◽

pp. 3629-3639 ◽

Cited By ~ 32

Author(s):

Laurent Genestier ◽

Romain Paillot ◽

Nathalie Bonnefoy-Berard ◽

Geneviéve Meffre ◽

Monique Flacher ◽

...

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

T Lymphocytes ◽

Heavy Chain ◽

Hla Class I ◽

Class I ◽

T Cell Proliferation ◽

Activated T Cells ◽

Hla Class I Molecules

Abstract In addition to their major function in antigen presentation and natural killer cell activity regulation, HLA class I molecules may modulate T-cell activation and proliferation. Monoclonal antibodies (MoAbs) that recognize distinct epitopes of HLA class I molecules were reported to interfere with T-cell proliferation. We show here that two MoAbs (mouse MoAb90 and rat YTH862) that bind to an epitope of the α1 domain of HLA class I heavy chain induce apoptotic cell death of activated, but not resting, peripheral T lymphocytes. Other reference anti-HLA class I antibodies specific for distinct epitopes of the α1 (B9.12.1), α2 (W6/32), or α3 (TP25.99) domains of the heavy chain decreased T-cell proliferation but had little or no apoptotic effect. Apoptosis shown by DNA fragmentation, phosphatidylserine externalization, and decrease of mitochondrial transmembrane potential was observed whatever the type of T-cell activator. Apoptosis did not result from Fas/Fas-L interaction and distinct though partly overlapping populations of activated T cells were susceptible to Fas– and HLA class I–mediated apoptosis, respectively. Induction of apoptosis did not require HLA class I cross-linking inasmuch as it could be observed with monovalent Fab′ fragments. The data indicate that MoAb90 and YTH862 directed against the α1 domain of HLA class I trigger apoptosis of activated T lymphocytes by a pathway which does not involve Fas-ligand.

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HLA class I restricted cytotoxic T cells in acute viral hepatitis type B

Journal of Hepatology ◽

10.1016/0168-8278(91)91031-b ◽

1991 ◽

Vol 13 ◽

pp. S11 ◽

Cited By ~ 1

Author(s):

A. Bertolettl ◽

C. Ferrari ◽

A. Penna ◽

F. Flaccaduri ◽

H.J. Schlicht ◽

...

Keyword(s):

T Cells ◽

Viral Hepatitis ◽

Acute Viral Hepatitis ◽

Cytotoxic T Cells ◽

Hla Class I ◽

Class I ◽

Type B ◽

Hepatitis Type B

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Human CD8 transgene regulation of HLA recognition by murine T cells.

Journal of Experimental Medicine ◽

10.1084/jem.182.5.1315 ◽

1995 ◽

Vol 182 (5) ◽

pp. 1315-1325 ◽

Cited By ~ 32

Author(s):

D M LaFace ◽

M Vestberg ◽

Y Yang ◽

R Srivastava ◽

J DiSanto ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Hla Class I ◽

Cell Receptor ◽

Class I ◽

Antigenic Peptides ◽

Cell Repertoire ◽

Repertoire Selection ◽

Hla Class I Molecules ◽

Cell Expression

A series of human CD8 transgenic (hCD8 Tg) mice with differential expression in the thymus and periphery were produced to investigate CD8 coreceptor regulation of repertoire selection and T cell responses. Expression of hCD8 markedly enhanced responses to both HLA class I molecules and hybrid A2/Kb molecules providing functional evidence for a second interaction site, outside of the alpha 3 domain, which is essential for optimal coreceptor function. Peripheral T cell expression of hCD8 was sufficient to augment responsiveness to HLA class I, as hCD8 Tg mice which lacked thymic expression responded as well as mice expressing hCD8 in the thymus and periphery. Both murine CD8+ and CD4+ T cells expressing hCD8 transgenes exhibited markedly enhanced responses to foreign HLA class I, revealing the ability of T cell receptor repertoires selected on either murine class I or class II to recognize human class I major histocompatibility complex (MHC). In contrast to recognition of foreign class I, thymic expression of hCD8 transgenes was absolutely required to enhance recognition of antigenic peptide restricted by self-HLA class I. Thus, our studies revealed disparate requirements for CD8 coreceptor expression in the thymus for selection of a T cell repertoire responsive to foreign MHC and to antigenic peptides bound to self-MHC, providing a novel demonstration of positive selection that is dependent on human CD8.

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The pockets guide to HLA class I molecules

Biochemical Society Transactions ◽

10.1042/bst20210410 ◽

2021 ◽

Author(s):

Andrea T. Nguyen ◽

Christopher Szeto ◽

Stephanie Gras

Keyword(s):

T Cells ◽

Cell Surface ◽

Peptide Binding ◽

Hla Class I ◽

Class I ◽

Side Chains ◽

Binding Prediction ◽

Peptide Residue ◽

Hla Class I Molecules ◽

Binding Pockets

Human leukocyte antigens (HLA) are cell-surface proteins that present peptides to T cells. These peptides are bound within the peptide binding cleft of HLA, and together as a complex, are recognised by T cells using their specialised T cell receptors. Within the cleft, the peptide residue side chains bind into distinct pockets. These pockets ultimately determine the specificity of peptide binding. As HLAs are the most polymorphic molecules in humans, amino acid variants in each binding pocket influences the peptide repertoire that can be presented on the cell surface. Here, we review each of the 6 HLA binding pockets of HLA class I (HLA-I) molecules. The binding specificity of pockets B and F are strong determinants of peptide binding and have been used to classify HLA into supertypes, a useful tool to predict peptide binding to a given HLA. Over the years, peptide binding prediction has also become more reliable by using binding affinity and mass spectrometry data. Crystal structures of peptide-bound HLA molecules provide a means to interrogate the interactions between binding pockets and peptide residue side chains. We find that most of the bound peptides from these structures conform to binding motifs determined from prediction software and examine outliers to learn how these HLAs are stabilised from a structural perspective.

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