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Review
. 2007 Aug;19(4):236-44.
doi: 10.1016/j.smim.2007.04.003. Epub 2007 Jun 4.

A role for "self" in T-cell activation

Michelle Krogsgaard  1 , Jeremy Juang, Mark M Davis
Affiliations
Review

A role for "self" in T-cell activation

Michelle Krogsgaard et al. Semin Immunol. 2007 Aug.

Abstract

The mechanisms by which alphabeta T-cells are selected in the thymus and then recognize peptide MHC (pMHC) complexes in the periphery remain an enigma. Recent work particularly with respect to quantification of T-cell sensitivity and the role of self-ligands in T-cell activation has provided some important clues to the details of how TCR signaling might be initiated. Here, we highlight recent experimental data that provides insights into the initiation of T-cell activation and also discuss the main controversies and uncertainties in this area.

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Figures

Fig. 1
Fig. 1. Models for the initiation of T-cell activation
Three different models for how T-cell activation is initiated. A. The coreceptor model in which T-cell activation is initiated by monomeric pMHC together with CD4 and TCR. B. The pseudodimer model, in which agonist-endogenous peptide-MHC heterodimers, stabilized by the co-receptor CD4, are crucial intermediates for triggering T lymphocytes. C. The dimers of dimers model where the signaling complex consists of two agonist pMHC complex, two TCRs and two CD4 molecules.
Fig. 2
Fig. 2. Self-peptide-MHC accumulation at the immunological synapse
A. To detect the accumulation of endogenous pMHC at the T-cell-APC interface APCs are pulsed with biotinylated self-peptides in the presence of minute amounts of unlabeled agonist peptide and the resulting biotin pMHC is labeled with streptavidin-Cy3, which can be detected with 3D fluorescence microscopy. B. Representative illustrations of pMHC accumulation at the T-cell-APC interface. The upper panel shows differential interference contrast images overlaid with Ca2+ ratio images obtained with fura-2 (340/380 excitations) and the lower panel show the en face view of a 3D reconstruction of Cy3-labeled pMHC. K5 is a strong agonist peptide, ER60, B2M, HSP self-peptides and 99A and 99E “null” peptide (from1).
Fig. 3
Fig. 3. Self-agonist peptide dimers as the basic signaling unit for T-cell signaling in CD4+ T cells
Experiments from Krogsgaard et al. show that the basic unit for initiation of T-cell signaling is a heterodimer of self and an agonist peptide MHC. A. Soluble self pMHC molecules where cross-linked to agonist pMHC (K5) using synthetic crosslinkers as previously described by Cochran et al.. Soluble heterodimers where mixed with T-cell blasts and based on the ratiometric analysis of fura-2, the percentage of cell (n>100) with an elevated Ca2+ signal were determined. B. CHO-gpi-IEk APCs were pulsed with 100 μM mixture containing the indicated ratios of endogenous peptide to agonist peptide (MCC). C. Lipid bilayers containing B7-1 and ICAM-1 pulsed with 0.08 μM mixture containing the indicated ratio of self I-Ek to I-Ek-MCC. APCs or bilayers were presented to T-cell blasts loaded with fura-2 and the frequency of T cells with elevated Ca2+ signal were determined.
Fig. 4
Fig. 4. The contribution of CD4 to the recognition of self-peptide MHC heterodimers
A. Crystal structures from Reinherz and colleagues showing the orientation of the CD4 molecule with respect to the TCR-pMHC complex. This would preclude the CD4 molecule from being able to bind the same MHC molecule that the TCR is binding to. B. Mutagenesis strategy for understanding the molecular function of CD4 in recognition of self-agonist-heterodimers. A * symbol indicates the site of the mutation abrogating CD4 binding. C. Results of the mutagensis analysis. Soluble wildtype and mutated heterodimers were mixed with T cell blasts loaded with fura-2 and the frequency of T cells with elevated Ca2+ signal was determined.
Fig. 5
Fig. 5. Possible mechanism for the contribution of self-ligands to T-cell signaling
At least two possible roles can be envisaged for the self pMHC complexes that act as co-agonists for a particular TCR (from ref. 32). A. The “Structural option”. Self- pMHC may stabilize a conformation induced by the agonist pMHC which allows the phosphorylation of TCR1s CD3 signaling molecules. This could occur in a number of ways, but in the example shown we are proposing a ‘tilting‘ mechanism that might allow phosphorylation (**) to proceed. In this mechanism, phosphorylation of the second TCR does not occur because of the very short half-life of the TCR2-endogenous pMHC complex. B. The ‘Catalytic’ option, in this case the TCR1-agonist ligand complex acts similarly to the ‘active site’ of an enzyme with TCR2 and (TCR3 etc.) acting as ‘substrates’ and endogenous pMHC co-agonist as ‘co-factors’. Here a succession of TCR-CD3 complexes diffuse into the vicinity of the TCR1-agonist, become phosphorylated, and then rapidly dissociate. This would explain how even very high affinity (long half-life) TCRs could still signal efficiently.
Fig. 6
Fig. 6. The role of self peptides
The specificity and sensitivity of T-cell recognition is vital to the immune response. Self-peptides are presented in both in the thymus and in the periphery on antigen presenting cells. In the thymus self-peptides play an important role for positive and negative selection and we propose that this might be triggering by homodimers (positive selection) or heterodimers (negative selection) of pMHCs that act as co-agonist in the maintaining T cell homeostasis and viability in the periphery when antigen is not present by providing a tonic T-cell stimulation.
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References

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