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encore19850铜虫 (小有名气)
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[求助]
求助文献段落翻译，急，在线等~大谢各位，不用逐字逐句，尽量把中心意思说清楚就好。
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Both experimental animal studies and human data have revealed that age-associated immune declines are mainly due to diminished T cell reactivity, including a reduced capacity of T cells to proliferate and survive after TCR stimulation.14,15 Moreover, aged T cells exhibit decreased rescue from activation-induced cell death by co-stimulation.16 Therefore, it is important to understand how advancing age affects immune responses within the T cell compartment with respect to tumor immunity. Early reports regarding age-associated decline in the function of the T cell compartment described profound impairment of endogenous polyclonal T cell responses mediated by both CD4 and CD8 T cells.34–36 However, recent evidence suggests that there may be a functional difference on a cellular level between CD4 and CD8 T cells with age, particularly age-associated declines in T cell function occurring within CD4 T cells.37,38 CD4 T cells play an important role by mediating both humoral and cellular immune responses in antitumor immunity.39 Recent evidence has strongly suggested that the age-associated declines in CD4 T cells may contribute to the development of cancer in the elderly. The proliferative ability of naïve CD4 T cells from aged mice is significantly reduced, which may be associated with the reduced ability of CD4 T cells to secrete IL-2 and express the IL-2 receptor.40,41 In addition, surface-activation markers, including CD154, CD25, and CD62L located on the effector T cells derived from aged CD4 T cells, are significantly decreased compared with those derived from young CD4 T cells. These defects could be overcome by additional IL-2 treatment in vitro, suggesting that the set of defects may be ascribed to lower production of IL-2 by aged naïve T cells.42,43 One of the most notable age-associated changes in the peripheral T cell compartment is the decrease in the number of naïve T cells, which favors the increase of memory T cells. Advancing age is associated with an increased number of memory T cells; however, these cells are markedly defective in proliferation and cytokine production during recall responses. Haynes et al. found that memory T cells derived from old naïve CD4 T cells exhibit markedly reduced proliferation, cytokine production, and cognate helper function compared with those derived from young CD4 T cells.44 Furthermore, these aged memory T cells were largely nonfunctional, whereas young memory T cells retain their function in aged mice. The upregulation of surface-expressed inhibitory receptors (e.g., PD-1) may cause the agedependent functional decline in effector-memory T cells.45–47 CD8 T cells also play a crucial role in the control of antitumor immune responses, and ageassociated changes in CD8 T cell-mediated immune responses have been demonstrated. In addition to the increased frequency of memory-phenotype CD4 T cells with age, advancing age is also associated with the magnitude of the memory response in the CD8 T cell compartment. Previous studies have reported the accumulation of memory-phenotype CD8 T cells during aging both in animals and humans.48 However, several recent cellular-based studies in mice have revealed that the age-associated defects in CD8 T cell responses are not likely the consequence of changes that are intrinsic to CD8 T cells, and that the effector function of CD8 T cells remains intact during aging. In the study reported by Li et al., Agspecific CD8 T cell function was evaluated using both young and old TCR transgenic mice.49 Those authors showed that aged naïve CD8 T cells differentiated into cytotoxic T cells as efficiently as their young counterparts. Similarly, in the study performed by Lyse et al., CD8 T cell activation and effector function were examined using TCR transgenic mice.50 The above-mentioned authors also demonstrated an absence of intrinsic defects in the ability of aged naïve CD8 T cells to become primary effector T cells and to reject tumor challenges. These results indicate that the CD8 T cell function remains largely intact as a consequence of aging. Overall, these results suggest that, at least in mice, age-related alterations in the T cell compartment may be the consequence of the increased frequency of memory-phenotype T cells, rather than of the inherent decline in the function of T cells. Gamma-delta T cells are also considered important effector cells of the immune system. These T cells constitute 5%–10% of all T lymphocytes and play an important role in immune defense against microbial phathogens.51,52 Recent studies have also suggested that gamma-delta T lymphocytes may contribute to antitumor immune surveillance in the periphery.53–55 In contrast to the large majority of T cells, so-called alpha-beta T cells, this class of T cells recognizes small non-peptidic antigens via gamma-delta antigen receptors (TCR) in an MHC-unrestricted manner, suggesting that they could exert antitumor effects despite decreased expression of MHC and tumor antigens on cancer cells. Therefore, their potential application in cancer immunotherapy has generated considerable interest. Several studies have also demonstrated the numerical and functional impairment of gamma-delta T cells in the elderly. Caruso’s group has reported age-related numerical and functional alterations, as evidenced by the reduced number of circulating gamma-delta T cells, an impaired ability of in vitro expansion through different stimuli, enhanced expression of the early activation marker CD69, and increased production of tumor necrosis factor (TNF)- alpha by these cells in old people in comparison with young subjects.56 Similarly, in the study performed by Provinciali’s group, decreased numbers of circulating gamma-delta T cells was observed in old subjects, although the actual cytotoxic activity of sorted populations of the cells was preserved.57 Moreover, in their analysis of melanoma patient samples, they revealed that the absolute number of circulating gamma-delta T cells and the ability of in vitro expansion of these cells were significantly reduced in melanoma patients, whereas these numerical and functional impairments were not correlated with age.58 Further studies will be required to elucidate whether the age-related alterations of gamma-delta T cells contribute to the impairment of antitumor immune responses in the elderly. DENDRITIC CELL FUNCTION AND ANTITUMOR IMMUNITY IN AGING Dendritic cells (DCs) play a pivotal role in antitumor immunity by presenting tumor antigens to T cells, which results in the initiation of antigen-specific immune responses or immune tolerance.59 Both experimental and clinical studies have demonstrated that the ageassociated alterations in DC number and function may contribute to the impairment of immune function during aging. Decreased numbers or impaired function of DCs was demonstrated in aged mice. In several mouse strains, the numerical density of epithelial DC populations in aged mice was reduced compared with that observed in young mice.60–63 Age-associated phenotypic alteration of DCs has also been demonstrated. The surface expression of co-stimulatory molecules such as MHC class II molecules and the intercellular adhesion molecule-1 (ICAM-1) on DCs in aged mice was significantly lower compared with Tomihara et al. Page 3 Crit Rev Oncog. Author manuscript; available in PMC 2014 March 20. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript that observed in young mice.60 In addition, the stimulatory capacity of DCs in aged mice was reduced compared with that detected in young mice. Moreover, splenic DC number and DC generation from bone marrow precursors in mice with spontaneous murine prostate cancer decreased with age.64 Studies in humans have documented decreased numbers and dysfunction of DCs in the elderly. It has also been demonstrated that the density of human gingival epithelium DCs in the elderly is significantly lower compared with that detected in a younger group.65 Furthermore, it has been shown that decreased numbers of epidermal DCs in the elderly may be correlated with the development of skin cancer.66 Recent studies have revealed that although the number of myeloid DCs was not altered with age, the number of plasmacytoid DCs was significantly altered during aging. This suggests that the age-related alteration of plasmacytoid DCs plays a crucial role in the development of immune suppression in the elderly.67–69 Several reports have demonstrated differences in surface phenotype and function of monocyte-derived DCs between elderly and young individuals. Steger et al. reported an absence of differences in the expression of several surface antigens on peripheral blood monocyte-derived DCs in old compared with those in young subjects.70 Those authors also reported that monocyte-derived DCs from both the elderly and young have a similar capacity of antigen presentation and induced the antigen-specific T cell response equally.71 Lung et al. also reported that the generation of peripheral blood monocyte-derived DCs was similar in the elderly and young.72 These results suggest that DCs generated ex vivo from old subjects have the capacity to stimulate the immune response that is similar to that of young subjects. In contrast, there is increasing evidence that in vivo DCs in the elderly have impaired function and phenotypic alteration. Pietschmann et al. demonstrated the decreased expression of HLA-DR in the peripheral blood DCs of the elderly compared with the young, although the expression level of various other surface markers was not different between the two groups.73 Della Bella et al. reported that DCs in the elderly exhibit a more mature phenotype and reduced ability of cytokine production.69 Varas et al. showed a decrease in the level of several surface molecules, including MHC class II, CD86, CD40, and CD54 on thymic DCs from the elderly. In addition, these thymic DCs from old individuals had an impaired ability to induce allogeneic T cell responses.73,74 More recently, Grolleau-Julius et al. reported that DC-specific intracellular adhesion molecule type 3-grabbing, non-integrin (DC-SIGN), which has been identified as being expressed on APCs and having a function in T cell co-stimulation, decreased in aged DCs.75 Moreover, Castle et al. revealed that increased production of IL-10 in DCs in the elderly is associated with age-dependent impaired proliferation of peripheral mononuclear cells.76 Taking all these findings into consideration, ex vivo-generated DCs from precursor cells of old individuals are functionally and phenotypically similar to those from young individuals, whereas in vivo DCs in elderly subjects are phenotypically altered and functionally decreased compared with those of young subjects. Several other groups have shown that DCs from the frail elderly are functionally decreased compared with those from the healthy elderly.77 These results strongly indicate that ageassociated declines in DC function impair the efficacy of DC-mediated antitumor immunity in the elderly. Grolleau-Julius et al. reported the impaired induction of the antitumor immune response by aged DCs in a murine melanoma model.78 In their study, the growth of established melanoma tumors in mice injected with peptide-pulsed aged DCs was significantly faster than that of mice injected with peptide-pulsed young DCs. Similarly, Sharma et al. compared the vaccination efficacy of old and young DCs pulsed with apoptotic tumor cells in young recipients, and demonstrated that old DCs presented a significantly reduced antitumor response compared with young DCs.79 In addition to the intrinsic deficiencies observed in aged DC, several recent studies have demonstrated that DC function may be affected by the aging microenvironment indirectly. Shi et al. have reported that the antitumor efficacy of young DC-based vaccination in aged mice was significantly impaired compared with that observed in young mice.80 The decreased antitumor effect of DC vaccination in aged mice was potentially associated with increased number of NK1.1+CD3+NKT cells.80 In agreement with this report, Grolleau- Julius et al. suggested in their review that the efficacy of vaccination with young DCs was significantly decreased in aged melanoma tumor-bearing mice compared with that recorded in young melanoma tumor-bearing mice.78 Thus, alterations in DC-mediated antitumor T cell responses in aging are likely attributable to both intrinsic and environmental influences. |
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