Why do T cells need to bind self-antigen moderately?

Submitted by itsabenhere t3_yw939i in askscience

I know that during the positive selection of T cells, they need to bind with moderate affinity to MHC/self-antigen, versus not binding at all or binding with high affinity. If a T cell can bind self-antigen even moderately, wouldn't that likely create an autoimmune T cell? I'm confused about why this occurs.

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iayork t1_iwj02ps wrote

T cells have to bind to MHC plus peptide for their function; if they don’t bind at all, they’re never going to be useful. So this is screening for the basic ability to bind MHC.

Why don’t they get screened against MHC with no peptide, instead of MHC with self peptide? Because there’s effectively no such thing as empty MHC on the cell surface. MHC (either class I or II) needs peptide to reach the surface and remain stable.

By requiring moderate affinity to MHC plus self peptide and screening out high affinity binding, the thymus ensures that self peptide won’t be recognized with enough affinity to actually trigger a mature T cell (which has a different signaling threshold than the developing T cell), but also ensures that the receptor has a chance to bind to MHC plus something non-self.

Of course it’s a very low chance - the vast majority of T cells produced never find a target, and most may well not have any possible target in the entire universe of possible peptides - but that’s fine, there are plenty of other T cells in the immune repertoire ocean.

T cell development is a reminder of how weird evolution’s solutions can be, to our human eyes. But it’s worked pretty well for 400 million years so far.

(As usual this is all wildly oversimplified.)

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rhowsnc t1_iwk179s wrote

immunology professor boyfriend: “and if high affinity binding occurs in this scenario you’d develop an autoimmune disease.”

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iayork t1_iwkrllh wrote

Depends what he’s calling “this scenario”. OP is specifically asking about developing T cells in the thymus. Those do occasionally bind with high affinity to the MHC/self peptide combination in the thymus, and those T cells are destroyed - it’s a normal part of T cell development, aimed at preventing autoimmunity (because if those T cells were allowed to survive and become mature, functional T cells, they could indeed cause autoimmunity - though there are further checks and balances even there).

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