Role of class I molecules of the major histocompatibility complex in cytotoxic T-cell function in health and disease

AbstractOvercoming tumor-mediated immunosuppression and enhancing cytotoxic T-cell activity within the tumor microenvironment are two central goals of immuno-oncology (IO) drug discovery initiatives. However, exploratory assays involving immune components are often plagued by low-throughput and poor clinical relevance. Here we present an innovative ultra-high-content assay platform for interrogating T-cell-mediated killing of 3D multicellular tumor spheroids. Employing this assay platform in a chemical genomics screen of 1800 annotated compounds enabled identification of small molecule perturbagens capable of enhancing cytotoxic CD8+ T-cell activity in an antigen-dependent manner. Specifically, cyclin-dependent kinase (CDK) and bromodomain (BRD) protein inhibitors were shown to significantly augment anti-tumor T-cell function by increasing cytolytic granule and type II interferon secretion in T-cells in addition to upregulating major histocompatibility complex (MHC) expression and antigen presentation in tumor cells. The described biotechnology screening platform yields multi-parametric, clinically-relevant data and can be employed kinetically for the discovery of first-in-class IO therapeutic agents.

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The major histocompatibility complex-restricted antigen receptor on T cells. II. Role of the L3T4 product.

Journal of Experimental Medicine ◽

10.1084/jem.158.4.1077 ◽

1983 ◽

Vol 158 (4) ◽

pp. 1077-1091 ◽

Cited By ~ 208

Author(s):

P Marrack ◽

R Endres ◽

R Shimonkevitz ◽

A Zlotnik ◽

D Dialynas ◽

...

Keyword(s):

T Cells ◽

Major Histocompatibility Complex ◽

T Cell ◽

Cell Receptor ◽

Surface Expression ◽

High Avidity ◽

Low Doses ◽

Major Histocompatibility ◽

Histocompatibility Complex

We have examined the role of the murine homologue of Leu-3 T4, L3T4, in recognition of antigen in association with products of the major histocompatibility complex (Ag/MHC) by murine T cell hybridomas. A series of ovalbumin (OVA)/I-Ad-specific T cell hybridomas were ranked in their sensitivity to Ag/I by measuring their ability to respond to low doses of OVA, or their sensitivity to inhibition by anti-I-Ad antibodies. T cell hybridomas with low apparent avidity for OVA/I-Ad, i.e. that did not respond well to low concentrations of OVA and were easily inhibited by anti-I-Ad, were also easily inhibited by anti-L3T4 antibodies. The reverse was true for T cell hybridomas with apparent high avidity for Ag/MHC. We found that the presence of low doses of anti-L3T4 antibodies caused T cell hybridomas to respond less well to low doses of Ag, and to be more easily inhibited by anti-I-Ad antibodies. These results suggested that the role of the L3T4 molecule is to increase the overall avidity of the reaction between T cells and Ag-presenting cells. In support of this idea was the discovery of several L3T4- subclones of one of our L3T4+ T cell hybridomas, D0.11.10. The L3T4- subclones had the same amount of receptor for OVA/I-Ad as their L3T4+ parent, as detected by an anti-receptor monoclonal antibody. The L3T4- subclones, however, responded less well to low doses of OVA, and were more easily inhibited by anti-I-Ad antibodies than their L3T4/ parent. These results showed that the L3T4 molecule was not required for surface expression of, or functional activity of, the T cell receptor for Ag/MHC. The L3T4 molecule did, however, increase the sensitivity with which the T cell reacted with Ag/MHC on Ag-presenting cells.

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The Role of Peptides in T Cell Alloreactivity Is Determined by Self–Major Histocompatibility Complex Molecules

Journal of Experimental Medicine ◽

10.1084/jem.191.5.805 ◽

2000 ◽

Vol 191 (5) ◽

pp. 805-812 ◽

Cited By ~ 62

Author(s):

Reinhard Obst ◽

Nikolai Netuschil ◽

Karsten Klopfer ◽

Stefan Stevanović ◽

Hans-Georg Rammensee

Keyword(s):

T Cells ◽

Major Histocompatibility Complex ◽

T Cell ◽

Target Cells ◽

Major Histocompatibility ◽

Complex Molecules ◽

Mhc Molecules ◽

Histocompatibility Complex ◽

Alloreactive T Cells

By analyzing T cell responses against foreign major histocompatibility complex (MHC) molecules loaded with peptide libraries and defined self- and viral peptides, we demonstrate a profound influence of self-MHC molecules on the repertoire of alloreactive T cells: the closer the foreign MHC molecule is related to the T cell's MHC, the higher is the proportion of peptide-specific, alloreactive (“allorestricted”) T cells versus T cells recognizing the foreign MHC molecule without regard to the peptide in the groove. Thus, the peptide repertoire of alloreactive T cells must be influenced by self-MHC molecules during positive or negative thymic selection or peripheral survival, much like the repertoire of the self-restricted T cells. In consequence, allorestricted, peptide-specific T cells (that are of interest for clinical applications) are easier to obtain if T cells and target cells express related MHC molecules.

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