IMGT Lexique

Thymocyte selection

In contrast to the TcR repertoire of immature thymocytes which is vast and largely results from V-(D)-J recombination, the TcR repertoire expressed by mature T cells is largely devoid of autoreactivity and is restricted to recognizing foreign peptides in the context of self-MHC molecules [1].

In the thymus, immature CD4⁺ CD8⁺ (DP) thymocytes undergo three different fates depending from the T cell receptor specificity and avidity to the thymic ligands, although the differences can be relatively small.

No specificity for self-ligands (self-MHC + self-peptide) : no signal → "death by neglect".
High avidity for thymic ligands : signal → deletion (the thymocytes are physically or functionally deleted from the T cell repertoire) ("negative selection").
This requires:
- activation or induction of Nur 77/Nor-1 and caspases,
- implication of the MKK6-p38 and JNK signalling pathway.
Low avidity for thymic ligands : signal → survival and development to mature, functional, single-positive (CD4⁺ CD8^- or CD4^- CD8⁺) T cells ("positive selection").
This requires :
- activation or induction of members of the bcl-2/blc-XL family,
- implication of the p21 ras-raf-MKK1-ERK signalling pathway.

There is a kinetic threshold between negative and positive selection based on the longevity of the T cell receptor ligand complex (dwell time of the receptor with its ligand) [2]. High affinity TcR/ligand interactions would result in a dwell time that allows complete progression of the signalling pathway and the formation of late activation complexes, resulting in negative selection. In contrast, low-affinity interactions with short dwell times would result in premature attenuation of the signalling cascade and positive selection [3].

[1]	Sebzda, E. et al. Annu. Rev. Immunol. 17, 829-874 (1999).
[2]	Williams, C. B. et al. J. Exp. Med. 189, 1531-1544 (1999).
[3]	Love, P. E. and Shores, E. W. Immunity 12, 591-597 (2000).