Spatial coordination of CD8 and TCR molecules controls antigen recognition by CD8⁺ T‐cells

Abstract

The interactions between the TCR and peptides bound to class I MHC encoded molecules (pMHC) and a mechanism for CD8 cooperation in this process are reviewed. Observation of two TCR/CD8 populations with different lateral diffusion rate constants as well as two distinct association phases of class I MHC tetramers ((pMHC) 4 ) with T-cells suggest that the most efficient pMHC-T-cell association route corresponds to a fast tetramer binding to a colocalized CD8/TCR population, which apparently resides within membrane rafts. Thus, ligandcell association starts by pMHC binding to the CD8. This rather fast step promotes pMHC association with CD8-proximal TCRs and thereby enhances the overall association process. The model suggests that this raft-associated CD8-TCR subpopulation is responsible for evoking T-cell activation.

Kinetics of MHC-CD8 Interaction at the T Cell Membrane

“…However, the detail mechanisms of cooperation between CD8 and TCR are not yet clear (1). One hypothesis proposes that binding of one molecule (CD8 or TCR) holds MHC to an optimal configuration, thereby accelerating the association of the other molecule (TCR or CD8) to MHC (5,14). An alternative but related hypothesis proposes that binding of the second molecule (CD8 or TCR) to MHC stabilizes the interaction between the first molecule (TCR or CD8) and MHC, thereby decelerating the dissociation of both molecules from MHC (6,24).…”

“…This dual function provides an opportunity, but does not necessarily set a requirement, for TCR-MHC and MHC-CD8 interactions to affect each other. However, it is controversial whether coreceptor CD8 and TCR bind pMHC cooperatively or independently (3,5,7,(12)(13)(14)(15).…”

Manipulation of MHC-I/TCR Interaction for Immune Therapy

“…The proportion of the proximal and distal CD8 and TCR molecules can determine the capacity of a T-cell to respond to APCs carrying either low or high levels of cognate pMHC-I complexes (52). The CTL attracts target cell expressing pMHC-I also utilizes other antigen-independent major adhesion molecules, such as ICAM-1/2, LFA-1/2 and CD2.…”

Specific T-cell Activation in an Unspecific T-cell Repertoire

“…The concept of a highly promiscuous TCR is controversial and has met with skepsis that continues until the present day-assuaged at least partly by the accumulating evidence for tuning mechanisms, which allow the T cell to modulate its antigen sensitivity by adjusting the expression of surface molecules and intracellular signalling machinery [14][15][16][17][18][19][20] . Mathematical modelling of the TCR/peptide-MHC interaction has shown just how powerful these modulatory mechanisms are, and has led to a new concept of dynamic differential regulation of functional sensitivity.…”