Selective Antigen Presentation by Major Histocompatibility Complex Class I and II Molecules: A Hypothesis

The major histocompatibility complex (MHC) class I and II molecules (abbreviated as MCH-I and MHC-II) are specialized in antigen presentation. Unlike the T cell receptors (TCRs), which have great variability, the MHC-I and MHC-II molecules have very lim-ited variations. It is apparent that the MHC-I and MHC-II molecules per se do not have the built-in ability to distinguish the huge population of self-peptides from antigenic nonself-peptides. At present, the precise mechanism for the selective presentation of antigenic peptides by both MHC-I and MHC-II molecules is unclear. For an MHC-II molecule to gain the ability to selectively present antigenic (mostly foreign) peptides, it is hypothesized herein that all naïve CD4+ T cells in the body will release extracellular vesicles (EVs) which are specially designed for uptake by the antigen-presenting cells; these EVs contain mRNAs that will be translated into an intracellular version of the TCR proteins (iTCRII), which will help select antigenic peptides for presentation by the MHC-II molecules. Similarly, it is hypothesized that the activated CD4+ T cells will also release EVs which contain mRNAs for another intracellular version of the TCR pro-teins (iTCRI) which will help the infected somatic cells to select the antigenic peptides (mostly from invading pathogens) for presentation by the MCH-I molecules. Under-standably, while the iTCRII proteins will work closely with MHC-II molecules in the exogenous endocytic pathway, the iTCRI proteins will work closely with MHC-I mol-ecules in the endogenous pathway. In this paper, a few other related hypotheses are also proposed, which jointly offer a feasible cellular mechanism for the selective presentation of antigenic peptides by both MHC-I and MHC-II molecules. While the proposed hypotheses are supported by some experimental observations, it is hoped that these hypotheses will stimulate future experimental testing and enhance our un-derstanding of the complex process of antigen presentation.