T cell responses: mTOR mixes up a recipe for success

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How does mTOR integrate signals from antigen, costimulatory and cytokine receptors in CD8+ T cells?

The stimulation of naive CD8⁺ T cells to generate a successful effector response requires three main ingredients: antigen and co-stimulation for T cell activation and cytokine stimulation to determine the type of response. But like most recipes, the result depends on careful mixing. A new paper in Immunity describes how mammalian target of rapamycin (mTOR) has a crucial role in the blending of signals from these three types of instruction to determine effector versus memory CD8⁺ T cell responses.


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The transcription factor T-bet (also known as TBX21) is a master regulator of differentiation of type 1 CD8⁺ effector T cells — which produce interferon- gamma (IFN gamma ) — and its expression can be induced by interleukin-12 (IL-12). Although a previous study has indicated that mTOR has a role in the differentiation of effector versus memory CD8⁺ T cells (see Further reading), until now it has been unclear how cell surface signals from antigen, co-stimulatory and cytokine receptors are integrated in a transcriptional response and how mTOR functions in this pathway.

In this study, Rao and colleagues used naive OT-I T cell receptor (TCR)-transgenic CD8⁺ T cells stimulated with an adherent cell line expressing antigen specific for the OT-I TCR and the co-stimulatory molecule CD80 (BOK cells). The addition of IL-12 to the cell cultures resulted in robust IFN gamma production by the OT-I cells. This type 1 effector commitment depended on increased and, in particular, prolonged phosphorylation (activation) of mTOR and its downstream targets in the OT-I cells. Increased mTOR activity in the presence of IL-12 resulted from increased activity of the phosphoinositide 3-kinase (PI3K)–AKT pathway, which signals downstream of the receptors for all three types of instructive signal. Maintenance of mTOR activation by IL-12 also required signal transducer and activator of transcription 4 (STAT4).

So, mTOR is a target of the instructions for type 1 CD8⁺ effector T cell differentiation, but how is this converted to a transcriptional programme? This study showed that IL-12-induced increased mTOR phosphorylation downstream of PI3K–AKT is essential for the persistent expression of T-bet, which in turn determines the type 1 effector commitment of CD8⁺ T cells.

In addition, expression by OT-I cells of the transcription factor eomesodermin — which is inversely regulated with T-bet in memory versus effector CD8⁺ T cells — was decreased by the addition of IL-12 to OT-I–BOK cell cultures but could be increased by the inhibition of mTOR. Inhibition of mTOR, leading to a switch from T-bet to eomesodermin expression, blocked the maturation of CD8⁺ effector T cells but increased the number of OT-I cells with a memory-like phenotype, which produced memory responses after adoptive transfer.

Together, these results show that mTOR is a crucial point of integration in CD8⁺ T cells for the signals that programme effector versus memory differentiation, functioning as a rheostat that tunes the response to antigen and co-stimulation depending on the cytokine milieu. The elucidation of these signalling pathways could lead to new approaches for the beneficial modulation of CD8⁺ T cell responses.

Kirsty Minton

References

Rao, R. R. et al. The mTOR kinase determines effector versus memory CD8⁺ T cell fate by regulating the expression of transcription factors T-bet and eomesodermin. Immunity 7 Jan 2010 (10.1016/j.immuni.2009.10.010)
Minton, K. T cell responses: Quantity and quality control by mTOR. Nature Rev. Immunol. 9, 534 (2009) | Article |