David UsharauliWhy T Cell Tolerance Is Fixed from Birth
1. Unlike the innate immune system, which uses receptors to discriminate self from nonself based on biochemical features of the ligand (like LPS, foreign DNA, or foreign RNA)
2. the adaptive immune system, such as T cells, make self-nonself discrimination independently of the physical or biochemical properties of the ligand. T cells simply recognize small fragments of proteins called peptides, which are indistinguishable between self and foreign.
3. This raises a question: how can T cells assign a “nonself” property to a peptide that is otherwise not recognized as foreign by any other system? Is it a learning process like neurons in the central nervous system? The answer is no.
4. At the individual level, the immune system does not learn, and cannot learn, what is self and what is nonself under natural conditions. Learning occurs only at the evolutionary population level, but for an individual, it is fixed and unchangeable.
5. Any peptide presented by the thymus at birth is assigned the self category, and anything else is nonself. This assignment does not change for the rest of the individual’s life.
6. Of course, evolution allows random changes in the self-peptide pool through mutation, which is why individuals may differ in their T cell responses to antigens.
7. Initially, some thought that self-peptides appearing later in life should also be categorized as self, implying a dynamic learning process. This is incorrect.
8. All relevant self-peptides or their cross-reactive mimics that need to be assigned as self are already present at birth. No dynamic changes are necessary later.
9. Why must the self-peptide pool be fixed and static? Because otherwise, self-nonself discrimination at the T cell level would fail. The only way to separate peptides that are physically identical is temporal: peptides present at birth = self, peptides appearing later = nonself.
10. Thymic negative selection and thymus-derived Tregs work to maintain this rigid system of self-nonself discrimination. Another reason self cannot be dynamic: if a self-peptide appeared later in life, how would T cells know it is self?
11. Some argue that the appearance of new self-peptides in the absence of inflammation could inactivate T cells or induce Tregs to suppress reactions. This does not work, because the timing of new self-peptides cannot be perfectly controlled to occur only without inflammation.
12. To tolerate such peptides, the corresponding Tregs would already need to exist at birth. This implies that the peptides or their mimics are already present in the thymus, allowing Tregs to develop.
13. In summary: tolerance to self is a fixed, static system established at birth. It does not change dynamically during an individual’s life.
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