Cutting Edge: MHC Class II Expression by Pulmonary Nonhematopoietic Cells Plays a Critical Role in Controlling Local Inflammatory Responses

CD4 is a membrane glycoprotein on T lymphocytes that binds to the same peptide:major histocompatibility complex (MHC) class II molecule recognized by the antigen-specific receptor (TCR), thereby stabilizing interactions between the TCR and peptide;MHC class II complexes and promoting the localization of the src family tyrosine kinase p56lck into the receptor complex. Previous studies identified a solvent-exposed loop on the class II beta 2 domain necessary for binding to CD4 and for eliciting CD4 coreceptor activity. Here, we demonstrate that a second surface-exposed segment of class II is also critical for CD4 function. This site is in the alpha 2 domain, positioned in single class II heterodimers in such a way that it cannot simultaneously interact with the same CD4 molecule as the beta 2 site. The ability of mutations at either site to diminish CD4 function therefore indicates that specifically organized CD4 and/or MHC class II oligomers play a critical role in coreceptor-dependent T cell activation.

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Interleukin-19 Abrogates Experimental Autoimmune Encephalomyelitis by Attenuating Antigen-Presenting Cell Activation

Frontiers in Immunology ◽

10.3389/fimmu.2021.615898 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hiroshi Horiuchi ◽

Bijay Parajuli ◽

Hiroyasu Komiya ◽

Yuki Ogawa ◽

Shijie Jin ◽

...

Keyword(s):

Experimental Autoimmune Encephalomyelitis ◽

Mhc Class Ii ◽

Th17 Cell ◽

Cell Activation ◽

Inflammatory Responses ◽

Critical Role ◽

Autoimmune Encephalomyelitis ◽

Therapeutic Benefits ◽

Ms Pathogenesis ◽

Experimental Autoimmune

Interleukin-19 (IL-19) acts as a negative-feedback regulator to limit proinflammatory response of macrophages and microglia in autocrine/paracrine manners in various inflammatory diseases. Multiple sclerosis (MS) is a major neuroinflammatory disease in the central nervous system (CNS), but it remains uncertain how IL-19 contributes to MS pathogenesis. Here, we demonstrate that IL-19 deficiency aggravates experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by promoting IL-17-producing helper T cell (Th17 cell) infiltration into the CNS. In addition, IL-19-deficient splenic macrophages expressed elevated levels of major histocompatibility complex (MHC) class II, co-stimulatory molecules, and Th17 cell differentiation-associated cytokines such as IL-1β, IL-6, IL-23, TGF-β1, and TNF-α. These observations indicated that IL-19 plays a critical role in suppression of MS pathogenesis by inhibiting macrophage antigen presentation, Th17 cell expansion, and subsequent inflammatory responses. Furthermore, treatment with IL-19 significantly abrogated EAE. Our data suggest that IL-19 could provide significant therapeutic benefits in patients with MS.

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Defective major histocompatibility complex class II assembly, transport, peptide acquisition, and CD4+ T cell selection in mice lacking invariant chain expression.

Journal of Experimental Medicine ◽

10.1084/jem.177.6.1699 ◽

1993 ◽

Vol 177 (6) ◽

pp. 1699-1712 ◽

Cited By ~ 208

Author(s):

E K Bikoff ◽

L Y Huang ◽

V Episkopou ◽

J van Meerwijk ◽

R N Germain ◽

...

Keyword(s):

Major Histocompatibility Complex ◽

Mhc Class Ii ◽

Critical Role ◽

Class Ii ◽

Intact Protein ◽

Invariant Chain ◽

Major Histocompatibility ◽

Protein Antigens ◽

Histocompatibility Complex ◽

Class Ii Alpha

We used gene targeting techniques to produce mice lacking the invariant chain associated with major histocompatibility complex (MHC) class II molecules. Cells from these mice show a dramatic reduction in surface class II, resulting from both defective association of class II alpha and beta chains and markedly decreased post-Golgi transport. The few class II alpha/beta heterodimers reaching the cell surface behave as if empty or occupied by an easily displaced peptide, and display a distinct structure. Mutant spleen cells are defective in their ability to present intact protein antigens, but stimulate enhanced responses in the presence of peptides. These mutant mice have greatly reduced numbers of thymic and peripheral CD4+ T cells. Overall, this striking phenotype establishes that the invariant chain plays a critical role in regulating MHC class II expression and function in the intact animal.

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