T cell receptor revision

The initial diversification processes (somatic V(D)J recombination or gene conversion and nucleotide addition) occur in the primary lymphoid organ (thymus) and lead to very high diversity (> 10¹⁴) of TCRs, which are able to recognize almost any antigenic structure/sequence. The paradigm of adaptive immunity is that a single T cell is educated only in thymus and at the exit from thymus it can express only a single TCR with unique and definitive antigen specificity which cannot be modified. It is not correct since dual receptor T cells do exist in the periphery and the single receptor T cells can modify its specificity or regain a second TCR there.^[8][9][10] Those T cells recognizing self-structures (peptide/MHC complexes) are eliminated in the thymus immediately in a process of central tolerance, however it is not 100% effective again. As a result, there are many self-reactive T cells emigrating from thymus to the periphery and performing their effector functions there, including cytototoxic and helper activities, finally leading to autoimmunity. Peripheral tolerance is a mechanism controlling such autoreactive T cells in secondary lymphoid organs, blood circulation and all non-lymphoid tissues by different means. TCR revision process is generating much higher T cell plasticity in the development of the adaptive immune system than we have previously anticipated.

Activation-dependent T cell revision process is part of peripheral tolerance mechanisms if the new TCR specificity loses its autoreactive specificity as described in mouse transgenic^[11] and knock-in^[12][13] mouse models or in self-reactive conventional T cells in mouse^[13][14] or man.^[15] Since this process is random, it might also lead to de novo appearance of autoreactive TCRs on initially non-self reactive T cells or even switch between T cell lineages such as T regulatory cells and Th17 cells^[16] or gamma/delta and alpha/beta T cells.^[17]

The current knowledge on antigen receptor editing both in T cells and B cells is far from complete, but it has an essential impact on the central dogma of immunology - the control of adaptive immune cells, their specificity and regulation.