What is the role of positive and negative selection in T cell development, and where do they occur?

• A. Positive selection ensures T cells react with self-MHC; occurs in thymic cortex. Negative selection removes cells that react too strongly with self-antigen; occurs in thymic medulla.
• B. Positive selection eliminates self-reactive cells; occurs in thymic medulla. Negative selection ensures T cells react with self-MHC; occurs in thymic cortex.
• C. Positive selection selects for CD4 lineage; occurs in bone marrow. Negative selection eliminates all autoreactive cells; occurs in spleen.
• D. Positive selection removes nonfunctional T cells; occurs in thymus. Negative selection has no role.

Answer: (A)

The main idea is that T cell maturation in the thymus includes two clearance steps that shape a functional, self-tolerant repertoire. Positive selection happens in the thymic cortex. Here, developing T cells (thymocytes) must show their TCR can recognize self-MHC molecules presenting peptides. Those with enough affinity receive survival signals and continue development; those that don’t interact with self-MHC die by neglect. This step ensures the T cells can actually recognize antigens presented by self-MHC in the periphery. Positive selection also helps determine lineage: recognition of MHC class II tends toward CD4 fate, while recognition of MHC class I tends toward CD8 fate.

Negative selection takes place in the thymic medulla. Thymocytes that bind self-peptide–MHC complexes with high affinity are induced to die, preventing autoreactive T cells from entering the circulation. This is central tolerance, aided by medullary thymic epithelial cells that express a wide array of tissue-restricted antigens (via AIRE) to expose developing T cells to self-components.

So, positive selection ensures functional MHC recognition and survival in the cortex, while negative selection eliminates highly self-reactive cells in the medulla to prevent autoimmunity.