Co-receptors and recognition of self at the immunological synapse

Abstract

The co-receptors CD4 and CD8 are important in the activation of T cells primarily because of their ability to interact with the proteins of the MHC enhancing recognition of the MHC-peptide complex by the T cell receptor (TCR). An antigen-presenting cell presents a small number of antigenic peptides on its MHC molecules, in the presence of a much larger number of endogenous, mostly nonstimulatory, peptides. Recent work has demonstrated that these endogenous MHC-peptide complexes have an important role in modulating the sensitivity of the TCR. But the role of the endogenous nonstimulatory MHC-peptide complexes differs in MHC class I and class II-restricted T cells. This chapter discusses the data on the role of CD4 or CD8 co-receptors in T cell activation at the immunological synapse, and the role of non stimulatory MHC-peptide complexes in aiding antigen recognition.

Fig. 1

CD4 co-receptor recruitment to the immunological synapse and FRET between TCR and CD4. (a), (b) show a time course of interaction between T cell and an APC presenting antigenic peptide. (c), (d) show the same with an APC that does not present the antigenic peptide. (a), (c) show the FRET response between CD3ζ–CFP and CD4–YFP, using a heat scale (Zal et al. 2002). (b), (d) show the fluorescence of the CD3ζ–CFP (green) and CD4–YFP (red). Only the antigenic stimulation causes close interaction between TCR and CD4, as reported by FRET between CD3ζ–CFP and CD4–YFP (a versus c), though both APCs recruited CD4 to the immunological synapse (b and d). Recruitment was much slower in the absence (d) versus the presence (d) of antigen. Reproduced with permission from Zal et al. (2002)

Fig. 2

Increased T-cell activation by endogenous nonstimulatory peptides at limiting antigen quantities. (a) shows the amount of TCR endocytosis at differing quantities of antigen OVA–K^b expressed on the cell surface of RMA-S cells, either alone or with added nonstimulatory peptides derived from VSV, Erk, or the P815 tumor antigen. Erk and P815 are natural endogenous K^b–binding peptides (Santori et al. 2002). (b) shows the percentage of T cells in conjugates with RMA-S cells treated as in (a). (c) shows the interaction between TCR and CD8 by the FRET signal between CD3ζ–CFP and CD8β–YFP. Used with permission from Yachi et al. (2005)

Fig. 3

The ability of nonstimulatory MHC–peptide ligands to enhance antigen recognition depends on their quantity rather than their sequence. A small amount of antigen was added to RMA-S cells (OVA). This resulted in very low expression of the epitope for the anti-OVA–K^b. Other nonstimulatory peptides were titrated in to increase the overall amount of K^b expression. This increased expression of K^b correlated with increased activation of thymocytes. Used with permission from Yachi et al. (2007)

Fig. 4

Endogenous peptides on RMA cells support antigen recognition. RMA and RMA-S cells were incubated with titrated amounts of antigen (OVA peptide) and used to stimulate naïve CD8⁺ T cells expressing the OT-I anti-OVA–K^b TCR. CD69 upregulation was assessed as a function of expression of the OVA–K^b epitope recognized by the 25-D1.16 mAb (Porgador et al. 1997). Used with permission from Yachi et al. (2007)

Fig. 5

Models of co-receptor function in T-cell activation. For consistency, these are all drawn using CD8 as the co-receptor. However, the pseudodimer model (b) is derived from studies of CD4⁺ MHC class II-restricted T cells (Krogsgaard et al. 2005). (a) The “classical” model where the co-receptor stabilizes the interaction between TCR and antigenic MHC–peptide. (b) The “pseudodimer” model, where co-receptor cross-links two TCRs, one interacting with antigenic MHC–peptide, and the other interacting with endogenous MHC–peptide. (c) The “pre-concentration” model, where the co-receptor interaction with antigenic or nonstimulatory MHC–peptide causes concentration of MHC–peptide, co-receptor, and Lck to the synapse

Fig. 6

The ability of nonstimulatory peptides to enhance antigen-recognition is independent of agonist strength. RMA-S cells were loaded with titrated amounts of antigen (OVA; a), a weaker agonist (Q4; b) or a very weak agonist (T4; c) in the absence or presence of various endogenous K^b-binding, OT-I nonstimulatory peptides (Santori et al. 2002). The upregulation of CD69 on prepositive selection thymocytes from OT-I transgenic Tap^−/− mice was assessed and expressed in relation to the expression of the OVA–K^b epitope of mAb 25-D1.16 mAb (Porgador et al. 1997). Used with permission from Yachi et al. (2007)