4.3.2 CD28 and CTLA-4: A Volume Control on T Cell ...
The use of a random repertoire of antigen receptors by T cells provides effective coverage for the recognition of evolving pathogens.However, it generates a significant problem: that of preventing such receptors recognizing self-tissues.Such self-reactivity can lead to potentially fatal autoimmune conditions including type-I diabetes, inflammatory bowel disorders, autoimmune cytopaenias and others.Whilst T cell selection in the thymus can remove some of these self-reactive specificities, it is incomplete for a variety of reasons.Therefore, significant numbers of potentially autoreactive T cells are present in the circulation of healthy individuals, at frequencies similar with other antigen specificities.Indeed, recent evidence suggests that tolerance to some tissue-restricted self-antigens cannot be achieved by deletion and relies on the presence of regulatory T cells.Thus, whilst thymic selection mitigates T cell self-reactivity,additional controls are required that involve the CD28/CTLA-4 system [10, 16].
The requirement for CD28 to co-stimulate T cell activation emerged from studies by Schwartz and Jenkins.Here, antigen specific T cells entered an unresponsive state, termed T cell anergy, in response to TCR stimuli in the absence of a “second signal”.This signal was subsequently identified as coming from the CD28 receptor interacting with CD80 or CD86.Since these ligands are up-regulated by a variety of inflammatory signals, CD28 signaling provides information on the inflammatory context or “danger” accompanying TCR recognition.Importantly, CD28 co-stimulation appears to be additive with signals via the TCR enhancing commitment to, as well as more rapid, cell division.Moreover, the requirement for CD28 co-stimulation is related to strength of TCR signaling such that strong TCR stimulation requires less co-stimulation.Thus,weak TCRs (such as those that are self-reactive) may be effectively controlled by constraining the availability of CD28 co-stimulation.These concepts relating to control of CD28 co-stimulation become significant when considering how CTLA-4 might function to quantitatively limit CD28 signaling thereby controlling self-reactive and tumour-reactive T cells in the absence of inflammation [10].
The importance of CD28 signaling in driving T cell proliferative responses has been strikingly reinforced by the recent identification of CD28 mutations in T cell leukaemias that increase its affinity for ligands.Here, point mutations with increased ligand affinity as well as direct CTLA-4-CD28 fusions have been observed generating high affinity CD28 variants, which presumably are less effectively out-competed by CTLA-4.A large body of work indicates that CD28 signals drive critical T cell effector functions by increasing the magnitude of T cell responses, stimulating metabolic changes as well as enhancing T cell differentiation and survival.CD28 signals also contribute to enhanced cytokine production, influence T cell migration and memory T cell responses to infections.Given these potent activating functions, it is apparent that effective control of CD28 co-stimulation is essential and can be provided by CTLA-4 [10, 17].(https://www.daowen.com)
The observation of fatal autoimmunity in CTLA-4 knockout mice resulting from the release of self-reactive T cells illustrated that CTLA-4 was a critical negative regulator of T cell responses.T cells isolated from knockout mice showed high levels of activation markers including CD25.Whilst the initial interpretation of this activated T cell phenotype focused on the possibility that CTLA-4 mediated an inhibitory signal preventing T cell activation, accumulating evidence now points to an important role for CTLA-4 in mediating the suppressive functions of Treg.Indeed,early experiments indicated that the major autoimmune phenotype of CTLA-4 deficient mice could be prevented by the presence of CTLA-4 expressing cells in mixed chimeras.This observation has been supported by a number of other experiments and a series of conditional and inducible CTLA-4 deletion experiments have confirmed that the major phenotype is consistent with an effector function for CTLA-4 on Treg.These data demonstrate that CTLA-4 on Treg can control the activity of other cells (such as APCs or naïve T cells) thereby, controlling fatal autoimmunity [10, 18].
Whilst CTLA-4 on Treg is clearly important in preventing autoimmunity, its expression is also induced on activated T cells.Evidence from knockout mice demonstrates a more severe phenotype in complete CTLA-4 knockouts compared to Treg specific knockouts, indicating an important role for CTLA-4 in conventional T cells.However, the function of CTLA-4 in non-Treg cells can also be cell extrinsic, suggesting they might use the same mechanism as Treg and activated Tcon can carry out trans-endocytosis.Nonetheless, cell-intrinsic functions of CTLA-4 controlling the homeostatic expansion of conventional T cells have been observed in vivo, although in vitro responses to stimulation were found to be similar between WT and knockout conventional T cells [10, 19].
It is also clear that CTLA-4 and CD28 directly influence Treg homeostasis.For example, CD28-deficient mice, or those where ligands are blocked, have reduced Treg numbers due to altered Treg generation and peripheral survival.Conversely, the loss of CTLA-4 from Treg promotes their expansion via increased CD28 signaling.Thus, both CD28 and CTLA-4 profoundly impact the generation, maintenance and function of Treg.This intimate connection between CD28 and CTLA-4 function means that it is difficult to understand manipulation of one receptor without considering the impact on the other.Indeed, it is arguable that understanding the impact of CTLA-4 manipulation is best appreciated in terms of its ultimate effect on CD28-CD80/CD86 interactions [21].