Evolution and Function of the Major Histocompatibility Complex

The major histocompatibility complex (MHC) class II-associated invariant chain (Ii) is thought to act as a chaperone that assists class II during folding, assembly, and transport. To define more precisely the role of Ii chain in regulating class II function, we have investigated in detail the biosynthesis, transport, and intracellular distribution of class II molecules in splenocytes from mice bearing a deletion of the Ii gene. As observed previously, the absence of Ii chain caused significant reduction in both class II-restricted antigen presentation and expression of class II molecules at the cell surface because of the intracellular accumulation of alpha and beta chains. Whereas much of the newly synthesized MHC molecules enter a high molecular weight aggregate characteristic of misfolded proteins, most of the alpha and beta chains form dimers and acquire epitopes characteristic of properly folded complexes. Although the complexes do not bind endogenously processed peptides, class II molecules that reach the surface are competent to bind peptides added to the medium, further demonstrating that at least some of the complexes fold properly. Similar to misfolded proteins, however, the alpha and beta chains are poorly terminally glycosylated, suggesting that they fail to reach the Golgi complex. As demonstrated by double label confocal and electron microscope immunocytochemistry, class II molecules were found in a subcompartment of the endoplasmic reticulum and in a population of small nonlysosomal vesicles possibly corresponding to the intermediate compartment or cis-Golgi network. Thus, although alpha and beta chains can fold and form dimers on their own, the absence of Ii chain causes them to be recognized as "misfolded" and retained in the same compartments as bona fide misfolded proteins.

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Tight Regulation of Major Histocompatibility Complex I for the Spatial and Temporal Expression in the Hippocampal Neurons

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.739136 ◽

2021 ◽

Vol 15 ◽

Author(s):

Yuqing Shen ◽

Jianqiong Zhang

Keyword(s):

Major Histocompatibility Complex ◽

Molecular Mechanisms ◽

Adult Brain ◽

Class I ◽

Major Histocompatibility ◽

Temporal Expression ◽

Class I Mhc ◽

Mhc I ◽

Histocompatibility Complex ◽

And Function

The expression and function of immune molecules, such as major histocompatibility complex (MHC), within the developing and adult brain have been discovered over the past few years. Studies utilizing classical class I MHC knockout animals suggest that these molecules, in fact, play essential roles in the establishment, function, and modification of synapses in the CNS. Altered neuronal expression of class I MHC, as has been reported in pathological conditions, leads to aberrations in neuronal development and repair. In the hippocampus, cellular and molecular mechanisms that regulate synaptic plasticity have heretofore been extensively studied. It is for this reason that multiple studies directed at better understanding the expression, regulation, and function of class I MHC within the hippocampus have been undertaken. Since several previous reviews have addressed the roles of class I MHC in the formation and function of hippocampal connections, the present review will focus on describing the spatial and temporal expression of class I MHC in developing, healthy adult, and aging hippocampus. Herein, we also review current literatures exploring mechanisms that regulate class I MHC expression in murine hippocampus. With this review, we aim to facilitate a deeper mechanistic understanding into the complex tight regulation of MHC I expression in hippocampus, which are needed as we explore the potential for targeting MHC I for therapeutic intervention in normal aging and in neurodegenerative diseases in the future.

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