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1.
Blood ; 143(18): 1856-1872, 2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38427583

RESUMEN

ABSTRACT: Allogeneic stem cell transplantation (alloSCT) is a curative treatment for hematological malignancies. After HLA-matched alloSCT, antitumor immunity is caused by donor T cells recognizing polymorphic peptides, designated minor histocompatibility antigens (MiHAs), that are presented by HLA on malignant patient cells. However, T cells often target MiHAs on healthy nonhematopoietic tissues of patients, thereby inducing side effects known as graft-versus-host disease. Here, we aimed to identify the dominant repertoire of HLA-I-restricted MiHAs to enable strategies to predict, monitor or modulate immune responses after alloSCT. To systematically identify novel MiHAs by genome-wide association screening, T-cell clones were isolated from 39 transplanted patients and tested for reactivity against 191 Epstein-Barr virus transformed B cell lines of the 1000 Genomes Project. By discovering 81 new MiHAs, we more than doubled the antigen repertoire to 159 MiHAs and demonstrated that, despite many genetic differences between patients and donors, often the same MiHAs are targeted in multiple patients. Furthermore, we showed that one quarter of the antigens are cryptic, that is translated from unconventional open reading frames, for example long noncoding RNAs, showing that these antigen types are relevant targets in natural immune responses. Finally, using single cell RNA-seq data, we analyzed tissue expression of MiHA-encoding genes to explore their potential role in clinical outcome, and characterized 11 new hematopoietic-restricted MiHAs as potential targets for immunotherapy. In conclusion, we expanded the repertoire of HLA-I-restricted MiHAs and identified recurrent, cryptic and hematopoietic-restricted antigens, which are fundamental to predict, follow or manipulate immune responses to improve clinical outcome after alloSCT.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Antígenos de Histocompatibilidad Clase I , Antígenos de Histocompatibilidad Menor , Humanos , Antígenos de Histocompatibilidad Menor/genética , Antígenos de Histocompatibilidad Menor/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/genética , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/genética , Linfocitos T/inmunología , Estudio de Asociación del Genoma Completo , Trasplante Homólogo , Femenino , Masculino
2.
EMBO J ; 40(16): e106540, 2021 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-34121210

RESUMEN

Dendritic cells (DC) subsets, like Langerhans cells (LC), are immune cells involved in pathogen sensing. They express specific antimicrobial cellular factors that are able to restrict infection and limit further pathogen transmission. Here, we identify the alarmin S100A9 as a novel intracellular antiretroviral factor expressed in human monocyte-derived and skin-derived LC. The intracellular expression of S100A9 is decreased upon LC maturation and inversely correlates with enhanced susceptibility to HIV-1 infection of LC. Furthermore, silencing of S100A9 in primary human LC relieves HIV-1 restriction while ectopic expression of S100A9 in various cell lines promotes intrinsic resistance to both HIV-1 and MLV infection by acting on reverse transcription. Mechanistically, the intracellular expression of S100A9 alters viral capsid uncoating and reverse transcription. S100A9 also shows potent inhibitory effect against HIV-1 and MMLV reverse transcriptase (RTase) activity in vitro in a divalent cation-dependent manner. Our findings uncover an unexpected intracellular function of the human alarmin S100A9 in regulating antiretroviral immunity in Langerhans cells.


Asunto(s)
Alarminas/genética , Calgranulina B/genética , VIH-1/fisiología , Células de Langerhans/virología , Virus de la Leucemia Murina de Moloney/fisiología , Infecciones por Retroviridae/prevención & control , Animales , Linfocitos T CD4-Positivos/inmunología , Línea Celular , Cricetulus , VIH-1/genética , Interacciones Huésped-Patógeno , Humanos , Células de Langerhans/inmunología , Leucemia Experimental/prevención & control , Ratones , Virus de la Leucemia Murina de Moloney/genética , Transcripción Reversa , Factor de Crecimiento Transformador beta/inmunología , Infecciones Tumorales por Virus/prevención & control , Replicación Viral
3.
Proc Natl Acad Sci U S A ; 119(29): e2119736119, 2022 07 19.
Artículo en Inglés | MEDLINE | ID: mdl-35858315

RESUMEN

In the current era of T cell-based immunotherapies, it is crucial to understand which types of MHC-presented T cell antigens are produced by tumor cells. In addition to linear peptide antigens, chimeric peptides are generated through proteasome-catalyzed peptide splicing (PCPS). Whether such spliced peptides are abundantly presented by MHC is highly disputed because of disagreement in computational analyses of mass spectrometry data of MHC-eluted peptides. Moreover, such mass spectrometric analyses cannot elucidate how much spliced peptides contribute to the pool of immunogenic antigens. In this Perspective, we explain the significance of knowing the contribution of spliced peptides for accurate analyses of peptidomes on one hand, and to serve as a potential source of targetable tumor antigens on the other hand. Toward a strategy for mass spectrometry independent estimation of the contribution of PCPS to the immunopeptidome, we first reviewed methodologies to identify MHC-presented spliced peptide antigens expressed by tumors. Data from these identifications allowed us to compile three independent datasets containing 103, 74, and 83 confirmed T cell antigens from cancer patients. Only 3.9%, 1.4%, and between 0% and 7.2% of these truly immunogenic antigens are produced by PCPS, therefore providing a marginal contribution to the pool of immunogenic tumor antigens. We conclude that spliced peptides will not serve as a comprehensive source to expand the number of targetable antigens for immunotherapies.


Asunto(s)
Antígenos de Neoplasias , Antígenos de Histocompatibilidad Clase I , Neoplasias , Complejo de la Endopetidasa Proteasomal , Empalme de Proteína , Linfocitos T , Presentación de Antígeno , Antígenos de Neoplasias/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Neoplasias/inmunología , Péptidos/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Linfocitos T/inmunología
4.
Best Pract Res Clin Haematol ; 37(2): 101555, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-39098803

RESUMEN

Allogeneic hematopoietic cell transplantation (alloHCT) provides a potential curative treatment for haematological malignancies. The therapeutic Graft-versus-Leukaemia (GvL) effect is induced by donor T cells attacking patient hematopoietic (malignant) cells. However, if healthy non-hematopoietic tissues are targeted, Graft-versus-Disease (GvHD) may develop. After HLA-matched alloHCT, GvL and GvHD are induced by donor T cells recognizing polymorphic peptides presented by HLA on patient cells, so-called minor histocompatibility antigens (MiHAs). The balance between GvL and GvHD depends on the tissue distribution of MiHAs and T-cell frequencies targeting these MiHAs. T cells against broadly expressed MiHAs induce GvL and GvHD, whereas those targeting MiHAs with hematopoietic-restricted expression induce GvL without GvHD. Recently, the MiHA repertoire identified in natural immune responses after alloHCT was expanded to 159 total HLA-I-restricted MiHAs, including 14 hematopoietic-restricted MiHAs. This review explores their potential relevance to predict, monitor, and manipulate GvL and GvHD for improving clinical outcome after HLA-matched alloHCT.


Asunto(s)
Enfermedad Injerto contra Huésped , Efecto Injerto vs Leucemia , Trasplante de Células Madre Hematopoyéticas , Antígenos de Histocompatibilidad Menor , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/inmunología , Antígenos de Histocompatibilidad Menor/inmunología , Antígenos de Histocompatibilidad Menor/genética , Efecto Injerto vs Leucemia/inmunología , Trasplante Homólogo , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/inmunología , Linfocitos T/inmunología , Aloinjertos
5.
Front Immunol ; 11: 659, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32362897

RESUMEN

Patients undergoing allogeneic stem cell transplantation as treatment for hematological diseases face the risk of Graft-versus-Host Disease as well as relapse. Graft-versus-Host Disease and the favorable Graft-versus-Leukemia effect are mediated by donor T cells recognizing polymorphic peptides, which are presented on the cell surface by HLA molecules and result from single nucleotide polymorphism alleles that are disparate between patient and donor. Identification of polymorphic HLA-binding peptides, designated minor histocompatibility antigens, has been a laborious procedure, and the number and scope for broad clinical use of these antigens therefore remain limited. Here, we present an optimized whole genome association approach for discovery of HLA class I minor histocompatibility antigens. T cell clones isolated from patients who responded to donor lymphocyte infusions after HLA-matched allogeneic stem cell transplantation were tested against a panel of 191 EBV-transformed B cells, which have been sequenced by the 1000 Genomes Project and selected for expression of seven common HLA class I alleles (HLA-A∗01:01, A∗02:01, A∗03:01, B∗07:02, B∗08:01, C∗07:01, and C∗07:02). By including all polymorphisms with minor allele frequencies above 0.01, we demonstrated that the new approach allows direct discovery of minor histocompatibility antigens as exemplified by seven new antigens in eight different HLA class I alleles including one antigen in HLA-A∗24:02 and HLA-A∗23:01, for which the method has not been originally designed. Our new whole genome association strategy is expected to rapidly augment the repertoire of HLA class I-restricted minor histocompatibility antigens that will become available for donor selection and clinical use to predict, follow or manipulate Graft-versus-Leukemia effect and Graft-versus-Host Disease after allogeneic stem cell transplantation.


Asunto(s)
Enfermedad Injerto contra Huésped/inmunología , Efecto Injerto vs Leucemia/inmunología , Antígenos de Histocompatibilidad Menor/metabolismo , Trasplante de Células Madre , Linfocitos T/inmunología , Alelos , Células Clonales , Estudio de Asociación del Genoma Completo , Enfermedad Injerto contra Huésped/genética , Efecto Injerto vs Leucemia/genética , Antígenos HLA-A/genética , Antígenos HLA-A/metabolismo , Antígenos HLA-B/genética , Antígenos HLA-B/metabolismo , Antígenos HLA-C/genética , Antígenos HLA-C/metabolismo , Humanos , Antígenos de Histocompatibilidad Menor/genética , Antígenos de Histocompatibilidad Menor/inmunología , Polimorfismo de Nucleótido Simple , Unión Proteica , Trasplante Homólogo
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