Altered Regulatory Capacity During Ageing

Immune function is also controlled by regulatory T and B cells and myeloid-derived suppressor cells (MDSCs), with emerging data suggesting that the functional competence of these regulatory cells is altered during ageing (Fig. 2.2). The most characterised of the regulatory subsets are the natural regulatory T cells (nTregs), defined as CD4+CD25hiFoxp3+ [58]. They are fundamental for maintaining peripheral tolerance and protection against autoimmunity, and also modulating immunity to infections and tumors [58]. Therefore, to maintain controlled immunity, it is important that this regulatory population is maintained throughout life. CD4+ nTregs are derived from the thymus, however, the thymus involutes with age [10] suggesting that nTreg numbers might also be reduced during aging. However, there is ample data to suggest that nTreg numbers increase with age [59-62]. Therefore the number of nTregs must either be sustained through extensive proliferation or by generation from an extrathymic source [60, 63]. Human nTregs can express either CD45RA or CD45RO,

Altered regulation of highly differentiated T cells during ageing

Fig. 2.2 Altered regulation of highly differentiated T cells during ageing. Tregs and MDSCs increase with age whereas Breg numbers have been shown to decline, all alter immune control leading to a loss of peripheral tolerance and increased autoimmunity, as well as modulating immune responses to infections with 90-95 % of adult nTregs displaying a CD45RO+ phenotype [64]. It has been shown that human CD45RO+ Tregs represent a highly differentiated population, characterised by short telomeres, a loss of telomerase activity and an increased susceptibility to apoptosis [60]. Indicating that these cells have limited capacity for self-renewal, suggesting that the Treg pool is not maintained through continuous turnover ofpre-existing CD45RO+ Tregs. Tregs can also be induced from CD4+CD25-Foxp3- conventional T cells in response to specific signals, such as TGFp and retinoic acid, these so called inducible Tregs (iTregs) display the same suppressive function as nTregs [65]. It has been shown that human Tregs share a close TCR homology with CD4+CD25- responder T cells [63, 66], supporting the hypothesis that the process of peripheral conversion from non-Tregs plays a significant role in the maintenance of the Treg population in humans. However mouse studies do not support this idea, when using non-immunised and non-lymphopenic mice, conversion was found not to play a significant role in the shaping of the peripheral Treg repertoire [67, 68]. Furthermore the induction of iTregs from aged mice was shown to be impaired [69]. However, the situation is likely to be different in humans, who undergo recurrent immunological challenges and have a much longer life span [65, 70].

Tregs belonging to the CD8+ T cell compartment are equally important in regulating immune responses, although they are less well characterised than their CD4+ counterparts [71]. Like CD4+ Tregs, the percentage of CD8+Foxp3+ Tregs significantly increases in older individuals, with suppressor function remaining comparable to younger individuals [72]. Interestingly, these CD8+ Tregs lacked expression of CD28, as discussed earlier the loss of CD28 is a hallmark of ageing. Thus suggesting that the increase in CD8+Foxp3+CD28- Tregs is consistent with the increase in overall numbers of CD8+CD28- T cells.

Over the past decade, a population of immunosuppressive B cells or Bregs have come to prominence, having been shown to inhibit excessive inflammation [73]. Bregs function primarily by skewing T cell differentiation in favour of a regulatory phenotype in both mice [74] and humans [75], controlling Treg induction through direct cognate interactions between Bregs and T cells [76,77]. Bregs can also suppress the expansion of pathogenic T cells through the production of IL-10, IL-35 and TGFp [78]. Although the expression of IL-10 has been used to define populations of Bregs, many different surface markers have been used, leading to inherent problems in Breg subset definition, reviewed by Rosser and Mauri [73]. However two phenotypically distinct subsets of B cells: transitional CD19+CD24hiCD38hi B cells [79] and CD19+CD5+CD1dhi ‘B10’ B cells [80] have been demonstrated to exert immunosuppressive functions. The frequency and function of both these Breg subsets declines with age, owing to reduced CD4+ T cell helper activity [81, 82]. The ability of Bregs isolated from old individuals to produce IL-10 following either ex vivo maturation or stimulation was also found to be reduced, and was linked to both impaired B cell signalling through CD40 and reduced expression of CD40L on CD4+ T cells [81].

More recently myeloid-derived suppressor cells (MDSCs) have also been recognised as a population of immunosuppressive myeloid lineage cells capable of suppressing T cell functions [83]. MDSCs have been characterised in mice as belonging to either a monocytic, CD11b+Ly6G-Ly6Chigh or granulocytic, CD11b+LyG6+Ly6Clow

lineage, with an analogous population being identified in humans, defined as CD33+HLA-DR- and lineage (CD3, CD19, CD56)-negative [84]. Reports have also shown human MDSCs to express CD11b and like their mouse counterparts have been subdivided into monocytic, CD14+ and granulocytic, CD15+ subtypes [85]. MDSCs suppress T cell responses principally through their ability to manipulate L+arginine metabolism, MDSCs produce arginase I, which catabolises L-arginine depriving T cells of this amino acid [83]. The loss of L-arginine from T cells in vitro inhibits their proliferation by arresting them in G0/Gi [86]. MDSCs can also inhibit CD8+ T cells through the production of ROS and peroxynitrite, which catalyze the nitration of the TCR, thereby preventing T cell-MHC interactions [87]. Furthermore MDSC can indirectly effect T cell activation through the induction of Tregs, this requires MDSC production of IL-10 and arginase, but depending on the subpopulation of MDSCs can either be TGFp dependent or independent [88]. The frequency of MDSCs increases in numerous cancers [89], chronic viral infections [90] and ageing [91]. The accumulation of MDSCs with age is thought to be driven by inflammation, the pro-inflammatory cytokines IL-ip and IL-6 and PGE2 all being shown to induce the differentiation of MDSCs [91].

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