Turning tumor cells in situ into T-helper cell-stimulating, MHC class II tumor epitope-presenters: immuno-curing and immuno-consolidation

Abstract Immature dendritic cells (DCs) specialize in antigen capture and maintain a highly dynamic pool of intracellular major histocompatibility complex class II (MHCII) that continuously recycles from peptide loading compartments to the plasma membrane and back again. This process facilitates sampling of environmental antigens for presentation to T helper cells. Here, we show that a signaling pathway mediated by the DC immunoreceptor tyrosine-based activation motif (ITAM)–containing adaptors (DAP12 and FcRγ) and Vav family guanine nucleotide exchange factors controls the half-life of surface peptide-MHCII (pMHCII) complexes and is critical for CD4 T-cell triggering in vitro. Strikingly, mice with disrupted DC ITAMs show defective T helper cell priming in vivo and are protected from experimental autoimmune encephalitis. Mechanistically, we show that deficiency in ITAM signaling results in increased pMHCII internalization, impaired recycling, and an accumulation of ubiquitinated MHCII species that are prematurely degraded in lysosomes. We propose a novel mechanism for control of T helper cell priming.

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T-Helper Cell-Response to MHC Class II-Binding Peptides of the Renal Cell Carcinoma-Associated Antigen RAGE-1

Immunobiology ◽

10.1016/s0171-2985(01)80003-6 ◽

2001 ◽

Vol 203 (5) ◽

pp. 743-755 ◽

Cited By ~ 10

Author(s):

Marike J.J.G. Stassar ◽

Laura Raddrizzani ◽

Jürgen Hammer ◽

Margot Zöller

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Mhc Class Ii ◽

Cell Response ◽

Renal Cell ◽

Class Ii ◽

T Helper Cell ◽

Helper Cell ◽

T Helper ◽

Binding Peptides

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Transforming Growth Factor β (TGF-β)-dependent Inhibition of T Helper Cell 2 (Th2)-induced Autoimmunity by Self–Major Histocompatibility Complex (MHC) Class II–specific, Regulatory CD4+ T Cell Lines

Journal of Experimental Medicine ◽

10.1084/jem.185.10.1769 ◽

1997 ◽

Vol 185 (10) ◽

pp. 1769-1775 ◽

Cited By ~ 124

Author(s):

Frank Bridoux ◽

Abdallah Badou ◽

Abdelhadi Saoudi ◽

Isabelle Bernard ◽

Elvira Druet ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Lines ◽

Mhc Class Ii ◽

Class Ii ◽

T Helper Cell ◽

Helper Cell ◽

T Helper ◽

Autoreactive T Cells ◽

T Cell Lines

Autoreactive anti–MHC class II T cells are found in Brown Norway (BN) and Lewis (LEW) rats that receive either HgCl2 or gold salts. These T cells have a T helper cell 2 (Th2) phenotype in the former strain and are responsible for Th2-mediated autoimmunity. In contrast, T cells that expand in LEW rats produce IL-2 and prevent experimental autoimmune encephalomyelitis, a cell-mediated autoimmune disease. The aim of this work was to investigate, using T cell lines derived from HgCl2-injected LEW rats (LEWHg), the effect of these autoreactive T cells on the development of Th2-mediated autoimmunity. The five LEWHg T cell lines obtained protect against Th2-mediated autoimmunity induced by HgCl2 in (LEW × BN)F1 hybrids. The lines produce, in addition to IL-2, IFN-γ and TGF-β, and the protective effect is TGF-β dependent since protection is abrogated by anti-TGF-β treatment. These results identify regulatory, TGF-β–producing, autoreactive T cells that are distinct from classical Th1 or Th2 and inhibit both Th1- and Th2-mediated autoimmune diseases.

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The influence of the HLA class II allele DQB1∗0301 on HCV specific T helper cell responses

Journal of Hepatology ◽

10.1016/s0168-8278(98)80573-4 ◽

1998 ◽

Vol 28 ◽

pp. 94 ◽

Cited By ~ 7

Author(s):

M.E. Cramp ◽

S. Rossol ◽

P. Carucci ◽

R. Williams ◽

N.V. Naoumov ◽

...

Keyword(s):

Class Ii ◽

Hla Class Ii ◽

T Helper Cell ◽

Helper Cell ◽

T Helper ◽

Cell Responses

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Specific T Helper Cell Requirement for Optimal Induction of Cytotoxic T Lymphocytes against Major Histocompatibility Complex Class II Negative Tumors

Journal of Experimental Medicine ◽

10.1084/jem.187.5.693 ◽

1998 ◽

Vol 187 (5) ◽

pp. 693-702 ◽

Cited By ~ 408

Author(s):

Ferry Ossendorp ◽

Erica Mengedé ◽

Marcel Camps ◽

Rian Filius ◽

Cornelis J.M. Melief

Keyword(s):

T Cells ◽

Tumor Cells ◽

Mhc Class Ii ◽

Cd4 T Cells ◽

Protective Immunity ◽

Class Ii ◽

T Helper ◽

Histocompatibility Complex ◽

Helper Epitope ◽

Antigen Presenting

This study shows that induction of tumor-specific CD4+ T cells by vaccination with a specific viral T helper epitope, contained within a synthetic peptide, results in protective immunity against major histocompatibility complex (MHC) class II negative, virus-induced tumor cells. Protection was also induced against sarcoma induction by acutely transforming retrovirus. In contrast, no protective immunity was induced by vaccination with an unrelated T helper epitope. By cytokine pattern analysis, the induced CD4+ T cells were of the T helper cell 1 type. The peptide-specific CD4+ T cells did not directly recognize the tumor cells, indicating involvement of cross-priming by tumor-associated antigen-presenting cells. The main effector cells responsible for tumor eradication were identified as CD8+ cytotoxic T cells that were found to recognize a recently described immunodominant viral gag-encoded cytotoxic T lymphocyte (CTL) epitope, which is unrelated to the viral env-encoded T helper peptide sequence. Simultaneous vaccination with the tumor-specific T helper and CTL epitopes resulted in strong synergistic protection. These results indicate the crucial role of T helper cells for optimal induction of protective immunity against MHC class II negative tumor cells. Protection is dependent on tumor-specific CTLs in this model system and requires cross-priming of tumor antigens by specialized antigen-presenting cells. Thus, tumor-specific T helper epitopes have to be included in the design of epitope-based vaccines.

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