Lessons from the bare lymphocyte syndrome: molecular mechanisms regulating MHC class II expression

Cell division cycle 42 (Cdc42) is a member of the Rho guanosine triphosphatase family and has pivotal functions in actin organization, cell migration, and proliferation. To further study the molecular mechanisms of dendritic cell (DC) regulation by Cdc42, we used Cdc42-deficient DCs. Cdc42 deficiency renders DCs phenotypically mature as they up-regulate the co-stimulatory molecule CD86 from intracellular storages to the cell surface. Cdc42 knockout DCs also accumulate high amounts of invariant chain–major histocompatibility complex (MHC) class II complexes at the cell surface, which cannot efficiently present peptide antigens (Ag’s) for priming of Ag-specific CD4 T cells. Proteome analyses showed a significant reduction in lysosomal MHC class II–processing proteins, such as cathepsins, which are lost from DCs by enhanced secretion. As these effects on DCs can be mimicked by chemical actin disruption, our results propose that Cdc42 control of actin dynamics keeps DCs in an immature state, and cessation of Cdc42 activity during DC maturation facilitates secretion as well as rapid up-regulation of intracellular molecules to the cell surface.

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Oxidation inhibits autophagy protein deconjugation from phagosomes to sustain MHC class II restricted antigen presentation

Nature Communications ◽

10.1038/s41467-021-21829-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Laure-Anne Ligeon ◽

Maria Pena-Francesch ◽

Liliana Danusia Vanoaica ◽

Nicolás Gonzalo Núñez ◽

Deepti Talwar ◽

...

Keyword(s):

Antigen Presentation ◽

Mhc Class Ii ◽

Antigen Processing ◽

Redox Regulation ◽

Molecular Mechanisms ◽

Class Ii ◽

Oxygen Species ◽

Cellular Processes ◽

Oxidative Inactivation ◽

Wide Range

AbstractLC3-associated phagocytosis (LAP) contributes to a wide range of cellular processes and notably to immunity. The stabilization of phagosomes by the macroautophagy machinery in human macrophages can maintain antigen presentation on MHC class II molecules. However, the molecular mechanisms involved in the formation and maturation of the resulting LAPosomes are not completely understood. Here, we show that reactive oxygen species (ROS) produced by NADPH oxidase 2 (NOX2) stabilize LAPosomes by inhibiting LC3 deconjugation from the LAPosome cytosolic surface. NOX2 residing in the LAPosome membrane generates ROS to cause oxidative inactivation of the protease ATG4B, which otherwise releases LC3B from LAPosomes. An oxidation-insensitive ATG4B mutant compromises LAP and thereby impedes sustained MHC class II presentation of exogenous Candida albicans antigens. Redox regulation of ATG4B is thereby an important mechanism for maintaining LC3 decoration of LAPosomes to support antigen processing for MHC class II presentation.

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Associations and Interactions between Bare Lymphocyte Syndrome Factors

Molecular and Cellular Biology ◽

10.1128/mcb.20.17.6587-6599.2000 ◽

2000 ◽

Vol 20 (17) ◽

pp. 6587-6599 ◽

Cited By ~ 67

Author(s):

Angela M. DeSandro ◽

Uma M. Nagarajan ◽

Jeremy M. Boss

Keyword(s):

Dna Binding ◽

Complex Formation ◽

Mhc Class Ii ◽

Protein Interactions ◽

Severe Combined Immunodeficiency ◽

Class Ii ◽

Bare Lymphocyte Syndrome ◽

Rich Domain ◽

Genes Encoding ◽

Rfx Complex

ABSTRACT The bare lymphocyte syndrome, a severe combined immunodeficiency due to loss of major histocompatibility complex (MHC) class II gene expression, is caused by inherited mutations in the genes encoding the heterotrimeric transcription factor RFX (RFX-B, RFX5, and RFXAP) and the class II transactivator CIITA. Mutagenesis of the RFX genes was performed, and the properties of the proteins were analyzed with regard to transactivation, DNA binding, and protein-protein interactions. The results identified specific domains within each of the three RFX subunits that were necessary for RFX complex formation, including the ankyrin repeats of RFX-B. DNA binding was dependent on RFX complex formation, and transactivation was dependent on a region of RFX5. RFX5 was found to interact with CIITA, and this interaction was dependent on a proline-rich domain within RFX5. Thus, these studies have defined the protein domains required for the functional regulation of MHC class II genes.

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Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome)

Cell ◽

10.1016/s0092-8674(05)80090-x ◽

1993 ◽

Vol 75 (1) ◽

pp. 135-146 ◽

Cited By ~ 362

Author(s):

Viktor Steimle ◽

Luc A. Otten ◽

Madeleine Zufferey ◽

Bernard Mach

Keyword(s):

Mhc Class Ii ◽

Class Ii ◽

Class Ii Transactivator ◽

Bare Lymphocyte Syndrome ◽

Mhc Class Ii Transactivator ◽

Mhc Class Ii Deficiency

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A block in the expression of MHC class II genes as the molecular basis for congenital immunodeficiency (‘bare lymphocyte syndrome’)

Cellular and Molecular Life Sciences ◽

10.1007/bf01975966 ◽

1986 ◽

Vol 42 (1) ◽

pp. 99-99

Author(s):

C. de Préval ◽

M. Loche ◽

B. Grospierre ◽

C. Griselli ◽

M. Hadam ◽

...

Keyword(s):

Mhc Class Ii ◽

Molecular Basis ◽

Class Ii ◽

Bare Lymphocyte Syndrome ◽

Congenital Immunodeficiency ◽

Mhc Class Ii Genes

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CD83 increases MHC II and CD86 on dendritic cells by opposing IL-10–driven MARCH1-mediated ubiquitination and degradation

Journal of Experimental Medicine ◽

10.1084/jem.20092203 ◽

2011 ◽

Vol 208 (1) ◽

pp. 149-165 ◽

Cited By ~ 120

Author(s):

Lina E. Tze ◽

Keisuke Horikawa ◽

Heather Domaschenz ◽

Debbie R. Howard ◽

Carla M. Roots ◽

...

Keyword(s):

Dendritic Cells ◽

Mhc Class Ii ◽

Molecular Mechanisms ◽

Costimulatory Molecule ◽

Class Ii ◽

Interleukin 10 ◽

Effective Vaccine ◽

Vaccine Adjuvants ◽

Mhc Ii ◽

Tm Domain

Effective vaccine adjuvants must induce expression of major histocompatability (MHC) class II proteins and the costimulatory molecule CD86 on dendritic cells (DCs). However, some adjuvants elicit production of cytokines resulting in adverse inflammatory consequences. Development of agents that selectively increase MHC class II and CD86 expression without triggering unwanted cytokine production requires a better understanding of the molecular mechanisms influencing the production and degradation of MHC class II and CD86 in DCs. Here, we investigate how CD83, an immunoglobulin protein expressed on the surface of mature DCs, promotes MHC class II and CD86 expression. Using mice with an N-ethyl-N-nitrosourea–induced mutation eliminating the transmembrane (TM) region of CD83, we found that the TM domain of CD83 enhances MHC class II and CD86 expression by blocking MHC class II association with the ubiquitin ligase MARCH1. The TM region of CD83 blocks interleukin 10–driven, MARCH1-dependent ubiquitination and degradation of MHC class II and CD86 in DCs. Exploiting this posttranslational pathway for boosting MHC class II and CD86 expression on DCs may provide an opportunity to enhance the immunogenicity of vaccines.

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Identification of Sulfavant A as the First Synthetic TREM2 Ligand Discloses a Homeostatic Response of Dendritic Cells After Receptor Engagement

10.21203/rs.3.rs-1211312/v1 ◽

2022 ◽

Author(s):

Carmela Gallo ◽

Emiliano Manzo ◽

Giusi Barra ◽

Laura Fioretto ◽

Marcello Ziaco ◽

...

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Mhc Class Ii ◽

Molecular Mechanisms ◽

Vaccine Development ◽

Class Ii ◽

Receptor Activation ◽

T Cell Response ◽

Adjuvant Effect ◽

Adjuvant Activity

Abstract The immune response arises from a fine balance of cellular and molecular mechanisms that provide for surveillance, tolerance, and elimination of dangers as pathogens. Improving the quality of the immune response remains a major goal in immunotherapy and vaccine development. Sulfavant A (SULF A) is a sulfolipid that has shown promising adjuvant activity in a cancer vaccine model. Here we report that SULF A is the first synthetic small molecule binding to the Triggering Receptor Expressed on Myeloid cells-2 (TREM2). The receptor engagement initiates an unconventional maturation of Dendritic cells (DCs) leading to upregulation of the Major Histocompatibility Complex class II (MHC Class II) and costimulatory molecules (CD83, CD86, DC54) without release of T helper type 1 (Th1) or 2 (Th2) cytokines. According to a TREM2 mechanism, this response is mediated by SYK-NFAT axis and is compromised by blockade and gene silencing of the receptor. Activation by SULF A preserved the DC functions to excite the allogeneic T cell response, and induced interleukin-10 (IL-10) release after lipopolysaccharide (LPS) stimulation. These results well support the adjuvant effect of SULF A and offer novel insights into the role of TREM2 in the differentiation of an unprecedented DC phenotype (homeDCs) that contributes to the maintenance of immune homeostasis without compromising lymphocyte activation and immunogenic response. The biological function of SULF-A may be of interest in various physiological and pathological processes involving the immune system.

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