Newly Discovered Cross-Penetration Pathway Bolsters Immune Response

A recent paper has helped to flesh out the details of a molecular mechanism used by immune dendritic cells to bolster the body’s ability to protect itself from infection.

Investigators at the University of British Columbia (Vancouver, Canada) used genetically engineered “knock-out” mice to study the CD74 cross-presentation pathway. The term cross-presentation denotes the ability of certain antigen-presenting cells to take up, process, and present extracellular antigens with MHC class I molecules to CD8 T-cells (cytotoxic T-cells).

Class I MHC molecules bind peptides generated mainly from degradation of cytosolic proteins by the proteasome. The MHC I:peptide complex is then inserted into the plasma membrane of the cell. The peptide is bound to the extracellular part of the class I MHC molecule. Thus, the function of the class I MHC is to display intracellular proteins to cytotoxic T cells (CTLs). However, class I MHC can also present peptides generated from exogenous proteins, in a process known as cross-presentation.

A normal cell will display peptides from normal cellular protein turnover on its class I MHC, and CTLs will not be activated in response to them due to central and peripheral tolerance mechanisms. When a cell expresses foreign proteins, such as after viral infection, a fraction of the class I MHC will display these peptides on the cell surface. Consequently, CTLs specific for the MHC:peptide complex will recognize and kill the presenting cell.

In the current study, which was published in the February 5, 2012, online edition of the journal Nature Immunology, the investigators reported the discovery of a CD74-dependent MHC class I cross-presentation pathway in dendritic cells that had a major role in the generation of MHC class I–restricted, CTL responses to viral protein– and cell-associated antigens. CD74 associated with MHC class I in the endoplasmic reticulum of dendritic cells and mediated the trafficking of MHC class I to endolysosomal compartments for loading with exogenous peptides.

“This could ultimately lead to a blueprint for improving the performance of a variety of vaccines, including those against HIV, tuberculosis, and malaria,” said senior author Dr. Wilfred Jefferies, professor of biology at the University of British Columbia. “This detailed understanding of the role of CD74 may also begin to explain differences in immune responses between individuals that could impact personalized medical options in the future.”

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