Seddon group

The active regulation of T cell homeostasis and quiescence

All stages of development, differentiation and function of T lymphocytes are regulated by cellular interactions with the environment. The clonotypic T cell receptor (TCR) plays a vital role in the interpretation of these environmental cues at all stages of T cell life. In the thymus, successful rearrangement of TCR β chains is signalled through the pre-TCRα complex during the process of β selection, signals through the TCR regulate positive selection and also help decide which mature subset the T cell will differentiate into. In the periphery, recognition of cognate antigen instigates a program of activation and differentiation that allow the T cell to perform its immunological functions, and the qualitative nature of the TCR signal during this process can influence how the activated T cell differentiates and also affect formation of long term memory.

Only recently, however, has it been recognised that the state of quiescence that naive T cells enter after development and before activation is not a passive one of awaiting antigenic stimulation but rather an active process requiring specific environmental cues and program of transcriptional activity. Naive B cells are maintained in a similar state of quiescence that requires survival signals through the B cell surface Ig receptor that are mediated through activation of the nuclear factor (NF)-κB pathway. Members of the kruppel zinc finger family of transcription factors, such as basic Kruppel-like factor, lung Kruppel-like factor (LKLF) and gut-Kruppel-like factor are thought to be important for maintaining this programmed state. Less is known about what maintains T cell quiescence but LKLF, expressed in mature thymocytes and peripheral T cells, is known to be important.

Figure 1

Homeostasis of peripheral T cells

The peripheral T cell pool is also maintained at a remarkable constant size and this is the result of tight homeostatic control regulated by environmental cues. The precise nature of these environmental signals varies depending on T cell subset and whether the T cell is in the naive or memory pool. Naive T cells require survival signals delivered by cytokines such as IL-7 and through interaction of TCR with self-peptide MHC complexes (spMHC). Competition for these survival factors limits the overall size of the naive T cell pool. However, these same signals can also trigger T cells to divide in situations when the T cell pool has suffered size reduction such as following an acute infection or as a consequence of medical interventions that result in lymphopoenia, e.g. treatment of malignancy. These homeostatic cell divisions can restore the number of naive T cells to normal levels. Therefore, in peripheral T cells, MHC dependent TCR signals can, remarkably, result in at least three different functional outcomes:

1. promotion of survival
2. cell division without activation
3. the instigation of a full program of activation and differentiation to effector state.

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