On T cell development, T cell signals, T cell specificity and sensitivity, and the autoimmunity facilitated by lymphopenia

Abstract

We propose a framework to explain how T cells achieve specificity and sensitivity, how the affinity of the TcR peptide/MHC interaction controls positive and negative thymic selection and mature T cell survival, and whether antigen-dependent activation and inactivation takes place. Two distinct types of signalling can lead to mature T cell multiplication. One requires the TcR to recognize with a certain affinity an antigen-derived peptide, an agonist peptide, bound to an MHC molecule. The other, the tonic signal, leads to naïve T cell survival and modest proliferation if the T cell successfully competes for endogenous, self-peptide/MHC ligands, involving lower affinity TCR/ligand interactions. Many suggest lymphopenia contributes to autoimmunity by increasing the strength of TcR-tonic signalling, and so activation of anti-self T cells. We suggest T cell activation requires antigen-mediated cooperation between T cells. Increased tonic signalling under lymphopenic conditions facilitates T cell proliferation and so antigen-dependent cooperation and activation of anti-self T cells.

On antigen‐specific signals, immune class regulation and energetics: Report III from the workshops on foundational concepts of immune regulation

“…We wrote two reports from the 2016 workshop, 1,2 and three attendants of the 2019 workshop further developed ideas on T cell sensitivity and specificity, a subject of much discussion at the workshop, as a paper. 3 This report is from the 2022 workshop. All participants are authors of the reports.…”

“…We have discussed previously that to achieve a successful self-non-self-discrimination requires that antigen receptors have a specificity for ligands that is not readily altered. 3 This could be achieved if TCR signals are perceived as digital (on/off). Nevertheless, a given T cell can perceive TCR signals in at least two different manners.…”

“…TCR signals can generate a full 'agonist' signal or instead a weaker tonic (subthreshold) signal. 3,38 Depending on the presence of other signals, the agonist signal can generate activation or tolerance. In contrast, the tonic signal leads to cell survival and, in some situations, modest proliferation, without substantial differentiation.…”

“…We discussed at the end of the workshop whether reports might be valuable to the broader immunological community. We wrote two reports from the 2016 workshop, 1,2 and three attendants of the 2019 workshop further developed ideas on T cell sensitivity and specificity, a subject of much discussion at the workshop, as a paper 3 . This report is from the 2022 workshop.…”

Immunology according to Dembic: Preserving integrity is key

“…However, it is known that co-inhibitory signals also exist (typically CTLA-4 and PD-1) and their blockade represented a breakthrough for cancer immunotherapy. A few other investigators have developed models that include co-inhibition 4,5 and tonic signalling, 6 but there is certainly room for more discussion and new ideas.…”