Structure of a covalently stabilized complex of a human alphabeta T-cell receptor, influenza HA peptide and MHC class II molecule, HLA-DR1

The murine γ-herpesvirus 68 has many similarities to EBV, and induces a syndrome comparable to infectious mononucleosis (IM). The frequency of activated CD8+ T cells (CD62Llo) in the peripheral blood increased greater than fourfold by 21 d after infection of C57BL/6J (H-2b) mice, and remained high for at least a further month. The spectrum of T cell receptor usage was greatly skewed, with as many as 75% of the CD8+ T cells in the blood expressing a Vβ4+ phenotype. Interestingly, the Vβ4 dominance was also seen, to varying extents, in H-2k, H-2d, H-2u, and H-2q strains of mice. In addition, although CD4 depletion from day 11 had no effect on the Vβ4 bias of the T cells, the Vβ4+CD8+ expansion was absent in H-2IAb–deficient congenic mice. However, the numbers of cycling cells in the CD4 antibody–depleted mice and mice that are CD4 deficient as a consequence of the deletion of MHC class II, were generally lower. The findings suggest that the IM-like disease is driven both by cytokines provided by CD4+ T cells and by a viral superantigen presented by MHC class II glycoproteins to Vβ4+CD8+ T cells.

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OS12.4.A MHC class II-restricted transgenic T cell receptor therapy targeting mutant capicua transcriptional repressor in experimental gliomas

Neuro-Oncology ◽

10.1093/neuonc/noab180.048 ◽

2021 ◽

Vol 23 (Supplement_2) ◽

pp. ii15-ii15

Author(s):

M Kilian ◽

M Friedrich ◽

K Sanghvi ◽

E Green ◽

S Pusch ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Mhc Class Ii ◽

Transcriptional Repressor ◽

Cell Receptor ◽

Class Ii ◽

Therapeutic Interventions ◽

Humanized Mice ◽

Adoptive Therapy

Abstract BACKGROUND Glioma subtypes are classified according to their characteristic mutations and show a high degree of resistance to standard therapeutic interventions such as radiotherapy and alkylating chemotherapy. Some of these characteristic mutations have shown to generate immunogenic neoepitopes that can be targeted with immunotherapy. 70% of oligodendrogliomas carry capicua transcriptional repressor (CIC) inactivating mutations. RESULTS In a screen for potential immunogenic glioma neoepitopes we identified recurrent CIC hotspot mutations at position 215 (CICR215W/Q) expressed in a subset of oligodendrogliomas as an immunogenic major histocompatibility complex (MHC) class II-restricted neoepitopes. Peptide-based vaccination of MHC-humanized mice resulted in the generation of robust mutation-specific T cell responses against CICR215W/Q, restricted to MHC class II. Droplet-based single cell T cell receptor (TCR) sequencing from CICR215W-specific T cell lines enabled retrieval of MHC class II-restricted CICR215W-reactive TCRs. By retroviral transduction of T cells, we established a flow cytometry-based testing platform of retrieved TCRs and were able to show the top reactive TCR against CICR215W to be shared between individual mice. Using a newly developed glioma model in MHC-humanized mice induced by CRISPR-based delivery of tumor suppressor targeting guide RNAs, we show that adoptive intraventricular transfer of CICR215W-specific TCR-transgenic T cells exert anti-tumor responses against CICR215W-expressing syngeneic gliomas. CONCLUSION The integration of immunocompetent MHC-humanized orthotopic glioma models in the discovery of shared immunogenic glioma neoepitopes facilitates the identification and preclinical testing of HLA-restricted neoepitope-specific TCRs for locoregional TCR-transgenic T cell adoptive therapy.

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The Final Maturation of at Least Some Single-Positive Cd4hiThymocytes Does Not Require T Cell Receptor–Major Histocompatibility Complex Contact

Journal of Experimental Medicine ◽

10.1084/jem.190.6.757 ◽

1999 ◽

Vol 190 (6) ◽

pp. 757-764 ◽

Cited By ~ 9

Author(s):

Ruben Dyall ◽

Janko Nikolić-Z̆ugić

Keyword(s):

Major Histocompatibility Complex ◽

T Cell ◽

T Cell Receptor ◽

Mhc Class Ii ◽

Cell Receptor ◽

Class Ii ◽

Class I ◽

Histocompatibility Complex ◽

Final Maturation ◽

Single Positive

The majority (∼70%) of postselection CD4+ single-positive (SP) thymocytes are CD8loCD4hi. These cells express very low levels of CD8, undetectable by flow cytofluorimetric (FCM) analysis, but sufficiently high to allow purification by panning. Unlike the fully mature CD8−CD4hi thymocytes, which account for the remaining ∼30% of the SP CD4+ thymocytes, CD8loCD4hi cells are functionally immature and short-lived unless they receive an unidentified maturation signal from the thymus. In this study, we tested the hypothesis that this signal is provided by a T cell receptor (TCR)–major histocompatibility complex (MHC) class II interaction. Using intrathymic transfer, we show that the immature CD8loCD4hi cells could complete their intrathymic maturation and populate the peripheral lymphoid organs in the absence of MHC class II (and class I) molecules. Furthermore, in mice devoid of class II (and class I) molecules, the progeny of CD8loCD4hi cells was long-lived and functionally reactive to allogeneic class II molecules, although their numbers in the spleen and the mesenteric lymph node were ∼40–50% lower than those in class II+ mice 5 mo after transfer. Control experiments demonstrated that the surviving cells did not originate from the contaminating mature thymocytes. These results demonstrate that the final maturation, proliferation, and peripheral survival (up to 5 mo) of at least some postselection CD4+ SP cells do not require the TCR–MHC class II interaction. They also indicate that the TCR–MHC class II interaction(s) required for the intrathymic development of long-lived CD4+ SP cells occurs before the CD4hi SP stage of development.

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