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Published in final edited form as: Ageing Res Rev. 2011 Feb 21;10(3):315–318. doi: 10.1016/j.arr.2011.01.005

Immunological hurdles of ageing: Indispensable research of the human model

Abbe N Vallejo 1,*
PMCID: PMC3098932  NIHMSID: NIHMS273791  PMID: 21315185

Abstract

Census reports of many countries indicate continuing trends for the graying of their populations. For the United States alone, persons aged ≥65 years are projected to comprise over 20% of the population by the year 2050. In view of the special medical needs of elders, scientific investigation into the biological aspects of aging is key towards the improvement of geriatric care for the coming decades. This special issue of Ageing Research Reviews focuses on advances in research on the immunology of human ageing. Herein are nine articles about the age-related alterations in both the innate and adaptive arms of the immune system, and about continuing hurdles in vaccinology. These articles point to a common theme that the immunological milieu in old age is substantially different from that seen in the young. This suggests that new development and/or innovation of immune-based clinical interventions for the elderly may need to be customized for their age group, rather than the mere adoption of therapies that have been designed for and/or tested for younger persons.

Introduction: Pandemic ageing of human populations

Since the latter half of the 20th century, many countries are witnessing the increased graying of their populations (UN-ESA, 2007). Japan currently has the largest proportion of older adults aged ≥65 years at ~23% that is projected to rise to ~40% by the year 2050 (Japan Statistics Bureau, 2010). For the United States, the current 12% of the population consisting of older adults is projected to also rise to 20% by the year 2050 (NCHS, 2010). Similarly, older adults comprise 21% of the current population of the European Union, with Sweden and Italy having largest numbers of old people (Grant et al., 2004). The elderly European population is projected to increase by 2050 at par with that of Japan due to phenomenal steady decline in birth rates for Japan and for the European Union member states (Grant et al., 2004; Japan Statistics Bureau, 2010). Demographic shifts towards the increasing numbers of elderly persons are not exclusive to industrialized countries, but it is a global phenomenon (CIA, 2010). Older adults are projected to comprise up to 25% and 15% of the aggregate population of developed and least developed countries, respectively, by 2050 (UN-ESA, 2005). Considering the myriad of age-related physiologic alterations, many of which are associated with age-related clinical syndromes (Stanziano et al., 2010), and the projected steady rise in the cost of geriatric medical care irrespective of country (Rice and Fineman, 2004; Payne et al., 2007; van Elk et al., 2010), ageing of the world population is a pandemic that present biomedical, socio-economic, and geopolitical challenges.

Immunity and ageing: Indispensability of human-based research

Immunity is a determinant of individual fitness, and the development of a diverse armamentarium of immune defenses is a modus operandi of speciation over millennia of evolution (McDade, 2003; McKean et al., 2008; Rosenstiel et al., 2009; Flajnik and Kasahara, 2010). In higher chordates, immune defenses, like other physiological systems, undergo dramatic changes over the lifetime of the individual. Human neonates have very distinct immune physiology from that of adults (Zaghouani et al., 2009), providing rationale for the traditional customization of immune interventions for infants and adolescents (de Brito et al., 2009). It is now clear that the immune system undergoes even more dramatic changes beyond adolescence and sexual maturity. With the increasing numbers of elderly humans, research on the immunology of ageing is paramount more than ever to facilitate efforts for the improvement of the quality of life of elders for the coming decades.

Animal models, principally the various genetic strains of the laboratory mouse, have been advancing knowledge on the immunology of ageing as in many areas of scientific investigation. Mouse models will undoubtedly remain to be useful tools in answering basic questions pertaining to the regulation, or dysregulation as might be the case, of immune processes with age.

However, it is important to emphasize that there are fundamental differences in the basic immunology of mice and humans (Mestas and Hughes, 2004). Such differences range from subtle regulatory controls to the stark species-specific contrast. An example of a subtle difference is the case for regulatory T cells for which mice have constitutive FOXP3+ and FOXP3-inducible subsets, but the human counterpart consists only of FOXP3-inducible cells (Ziegler, 2006). Examples of clear species-specific differences are the unique human (primate) genes encoding for killer cell immunoglobulin-like receptors (Parham et al., 2010); the unique subset of human marginal zone B cells (Weill et al., 2009); the lack of expression of CD56 on mouse natural killer cells (Hayakawa et al., 2006); and the activating versus inhibitory activity of B7-H3 in mouse and human T cells, respectively (Yi and Chen, 2009). And perhaps the best example of species-specific immunologic differences in the context on chronologic ageing is the case for CD28 that is expressed on T cells throughout the life of mice, but is progressively and irreversibly lost with ageing in humans (Vallejo, 2005). Such specific-differences underscore caution in the interpretation of observations from murine studies as to its applicability to human biology (Rosol et al., 2003; Downey and Cohen, 2009; Shedlock et al., 2009; Bodewes et al., 2010; Boudet, 2010).

The experimental setting is also significantly different between murine and human studies. Murine studies are generally conducted within the confines of a sanitized environment, and oftentimes involve the use of highly contrived genetic strains such as transgenics or knockouts. In contrast, the host and the environment in human studies are largely unmodified allowing assessment of “experiments of nature” that truly affect individual health and survival (Casanova and Abel, 2004). Ageing in the human immune system is such an experiment of nature. The nine articles in this special issue of Ageing Research Reviews discuss the results of observational immunology that may provide insights into stronger rationale for future translation efforts into the improvement of immune protection of the elderly.

Alterations of innate immune function with ageing

Two articles discuss the impact of age on the innate immune system. The first is by Shaw and colleagues (2010) delving on age-related properties of Toll-like receptors (TLR), the most primitive of the innate defenses. They report that while not all TLR function is adversely affected by age, there is insufficiency of signaling of particular TLRs that appears to be associated with dysregulation of protein trafficking rather than simple block of transcription or translation. Dysregulation of TLR trafficking is consistent with an emerging theme about progressive perturbation of the quality control of protein homeostasis as cells naturally undergo senescence, or more acutely within the context of pathologic states (Buchberger et al., 2010).

The second paper is by Agrawal and Gupta (2010) synthesizing research about age-related changes in dendritic cell (DC) function. Notably, they report diversity of human DC phenotypes, some of which have no obvious counterparts in the mouse. Depending on type of DC, functional deficits of DC function appear to be related to either the loss of DC numbers and/or signaling of particular receptors such DCs express. Considering that DCs serve as bridge between innate and adaptive immunity, ascertaining types and lineages of DC subsets remains a fundamental undertaking towards to the prospects of cell-based immunotherapy (Crozat et al., 2010). In the context of ageing, a key question is whether there is (are) particular DC subset(s) that could be harnessed to enhance its innate protective function and/or its capacity to prime cell-mediated immunity.

Age-related alteration in adaptive immune immunity

The paper by Frasca and colleagues (2010) examines the B cell compartment. They report about the increasing trend for the accumulation of functionally exhausted, switched-memory B cells with age. But more importantly, they also report that the proportion of naïve B cells increases with age. This phenomenon is not due to new B cell lymphoiesis, but to alteration in the immunoglobulin (Ig) class switching machinery. It appears that this pool of aged naïve B cells is much increased among centenarians (Colonna-Romano et al., 2010). An intriguing question then is whether there is yet an undiscovered role of naïve B cells that might perhaps be beneficial in extreme old age.

In the T cell compartment, age-related functional alterations are highlighted by the insufficiency of signaling. The paper by Larbi and colleagues (2010) synthesizes research on aged T cell signaling. They discuss primary signaling deficits of the T cell receptor (TCR)-CD3 complex, changes in costimulatory signals exemplified by the loss of CD28, altered cytokine signaling, and the impact of increased number of inhibitory receptors. The importance of these signaling studies is underscored by the impetus of translational efforts into intervening against age-related clinical syndromes (D’Antona and Nisoli, 2010; McCubrey et al., 2010).

Two papers discuss age-related changes in the T cell repertoire. The first is by Brunner et al (2010) summarizing repertoire changes within the context of persistent viral infections. Consistent with the notion of experiment in nature, they report that persistent viruses such as cytomegalovirus (CMV) impose natural pressure towards the accumulation of CMV-specific T cells throughout life. But due to persistent activation, many such antigen-specific T cells have pronounced functional defects and so they may not provide protection against CMV re-infection or re-activation. An important research footnote by the authors is the apparent difference in the pattern of CMV infection between Europe and US elderly populations. Europeans get infected with CMV more slowly and progressively with age, such that CMV seropositivity in old age has been associated with poor health outcomes among elderly Europeans (Wikby et al., 2005). In contrast, there is more widespread CMV seroprevalence within the US population due to CMV exposure at an early age (Bate et al., 2010). Hence, it will be of interest to examine whether CMV serology significantly impacts health outcomes of US elders. A curious notion is whether there might be a protective anti-CMV memory response among US seniors.

The second paper on T cell repertoire changes is by Vallejo and colleagues (2010). They summarize studies reporting the unusual increased expression of natural killer (NK) receptors on T cells with advancing age. They postulate that such NK-like T cells may be a compensatory mechanism for the phenomenal age-related contraction of TCR repertoire diversity and for the corresponding functional deficits of classical NK cells. It will therefore be of interest to examine the nature and the extent to which NK-like T cells contribute to protective immunity in old people, particularly in centenarians who appear to have a unique immune physiology (Sansoni et al., 2008). A challenge of course is to decipher whether and how a single, or multiple, NK-related receptors elicit T cell-driven protective responses either in a TCR-dependent or TCR-independent manner.

Challenges of vaccinology, and the importance of population-based studies

Considering the myriad changes in immune function with ageing, it is perhaps unsurprising that optimizing vaccine responses in the elderly remain a fundamental challenge. The papers by Lang et al (2010) and McElhaney (2010) discuss the continuing hurdles about vaccination against influenza. In the US, 90% of annual influenza-related deaths consist of older adults despite high vaccine coverage (CDC, 2010). Such demographic data underscore the ongoing controversy about the efficacy of flu vaccines, and for the wisdom, or lack thereof, for the public health policy of primarily targeting elderly people for seasonal flu vaccination. Efficacy of flu vaccines could be influenced by intrinsic clinical characteristic of the population receiving the vaccine. Thus, Lang et al notes the importance of assessing the health status of elders, and so mortality outcomes alone may not truly be indicative of vaccine efficacy. It might be time therefore for researchers and epidemiologists to better define immunologic and clinical criteria of what constitutes flu vaccine efficacy. McElhaney suggests that the usual measurement of vaccine antibody titers could be complemented with cellular measures of anti-flu responses. Clearly, much research is still needed to improve flu vaccine design for old people.

The paper by Singh and Newman (2010) provides an exhaustive review of population studies of aging. A common theme of these studies is the low-level systemic upregulation of inflammatory cytokines with age, with interleukin-6 being a strong predictor of disease and disability in many elderly populations. An important question then is whether inflammatory cytokines directly cause disability in old people, bearing in mind that young people with chronic inflammatory diseases such as rheumatoid arthritis have even higher magnitudes of systemic cytokine upregulation yet they do not seem to manifest the same forms of disability and clinical syndromes as old people. Considering the pleiotropic effects of cytokines, one thought is that the low-level systemic cytokine upregulation in old age indicates an immunologic environment wherein the quality of immune responses are influenced by the prevailing cytokine milieu.

Conclusion: Steadying the course of human-based research on the immunology of ageing

On the one hand, age clearly imposes drastic changes in immune physiology that contribute to poorer immune responsiveness of old people relative to younger people. On the other hand, older adults have heterogeneous health and immune phenotypes with increasing numbers of very old people in their 8th to 10th decade of life. Therefore, research on the immunology of ageing needs to go beyond the characterization of age-related immune deficiencies. Arguably, it remains to be examined whether there are unique of immune mechanisms that directly promote healthy ageing and/or maintain immune protection in old age. An interesting question is whether immune competence in old age could be genetically determined. Classical immune interventions such as vaccines may also need to be age-specific, rather than simply adopting intervention regimes used for younger people. Improvements of the quality of life of the growing population of older adults, through research progress on the immunology of ageing and in all biological aspects of ageing, are very much within reach. It may only be stifled by the continuous shrinking trend of funding for ageing research (Wadman, 2010).

Acknowledgments

Research is supported by the National Institutes of Health (R01 AG030734).

Footnotes

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References

  1. Agrawal A, Gupta S. Impact of aging on dendritic cell functions in humans. Ageing Res Rev. 2010 doi: 10.1016/j.arr.2010.06.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bate SL, Dollard SC, Cannon MJ. Cytomegalovirus seroprevalence in the United States: the national health and nutrition examination surveys, 1988–2004. Clin Infect Dis. 2010;50:1439–1447. doi: 10.1086/652438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bodewes R, Rimmelzwaan GF, Osterhaus AD. Animal models for the preclinical evaluation of candidate influenza vaccines. Expert Rev Vaccines. 2010;9:59–72. doi: 10.1586/erv.09.148. [DOI] [PubMed] [Google Scholar]
  4. Boudet F. Vaccines for the elderly: the quest for the ideal animal model. J Comp Pathol. 2010;142:S70–S73. doi: 10.1016/j.jcpa.2009.10.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brunner S, Herndler-Brandstetter D, Weinberger B, Grubeck-Loebenstein B. Persistent viral infections and immune aging. Ageing Res Rev. doi: 10.1016/j.arr.2010.08.003. [DOI] [PubMed] [Google Scholar]
  6. Buchberger A, Bukau B, Sommer T. Protein quality control in the cytosol and the endoplasmic reticulum: brothers in arms. Mol Cell. 2010;40:238–252. doi: 10.1016/j.molcel.2010.10.001. [DOI] [PubMed] [Google Scholar]
  7. Casanova JL, Abel L. The human model: a genetic dissection of immunity to infection in natural conditions. Nat Rev Immunol. 2004;4:55–66. doi: 10.1038/nri1264. [DOI] [PubMed] [Google Scholar]
  8. CDC (Centers for Disease Control and Prevention) Estimates of deaths associated with seasonal influenza --- United States, 1976–2007. MMWR Morb Mortal Wkly Rep. 2010;59:1057–1062. [PubMed] [Google Scholar]
  9. CIA (Central Intelligence Agency) The World Fact Book. 2010 Online book ISSN 1553–8133. Central Intelligence Agency, Washington, DC. https://www.cia.gov/library/publications/the-world-factbook/index.html.
  10. Colonna-Romano G, Buffa S, Bulati M, Candore G, Lio D, Pellicanò M, Vasto S, Caruso C. B cells compartment in centenarian offspring and old people. Curr Pharm Des. 16:604–608. doi: 10.2174/138161210790883750. [DOI] [PubMed] [Google Scholar]
  11. Crozat K, Guiton R, Guilliams M, Henri S, Baranek T, Schwartz-Cornil I, Malissen B, Dalod M. Comparative genomics as a tool to reveal functional equivalences between human and mouse dendritic cell subsets. Immunol Rev. 2010;234:177–198. doi: 10.1111/j.0105-2896.2009.00868.x. [DOI] [PubMed] [Google Scholar]
  12. D’Antona G, Nisoli E. mTOR signaling as a target of amino acid treatment of the age-related sarcopenia. Interdiscip Top Gerontol. 2010;37:115–141. doi: 10.1159/000319998. [DOI] [PubMed] [Google Scholar]
  13. de Brito CA, Goldoni AL, Sato MN. Immune adjuvants in early life: targeting the innate immune system to overcome impaired adaptive response. Immunotherapy. 2009;1:883–895. doi: 10.2217/imt.09.38. [DOI] [PubMed] [Google Scholar]
  14. Downey JM, Cohen MV. Why do we still not have cardioprotective drugs? Circ J. 2009;73:1171–1177. doi: 10.1253/circj.cj-09-0338. [DOI] [PubMed] [Google Scholar]
  15. Flajnik MF, Kasahara M. Origin and evolution of the adaptive immune system: genetic events and selective pressures. Nat Rev Genet. 2010;11:47–59. doi: 10.1038/nrg2703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Frasca D, Diaz A, Romero M, Landin AM, Blomberg BB. Age effects on B cells and humoral immunity in humans. Ageing Res Rev. 2010 doi: 10.1016/j.arr.2010.08.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Grant J, Hoorens S, Sivadasan S, van het Loo M, DaVanzo J, Hale L, Gibson S, Butz W. Low Fertility and Population Ageing Causes, Consequences, and Policy Options. Monogragh MG206-EC prepared for the European Commission; RAND Europe, Leiden, Netherlands: 2004. p. 178. http://www.rand.org/pubs/monographs/MG206.html. [Google Scholar]
  18. Hayakawa Y, Huntington ND, Nutt SL, Smyth MJ. Functional subsets of mouse natural killer cells. Immunol Rev. 2006;214:47–55. doi: 10.1111/j.1600-065X.2006.00454.x. [DOI] [PubMed] [Google Scholar]
  19. Japan Statistics Bureau. Statistical Handbook of Japan 2010. Vol. 17. Ministry of Internal Affairs and Communications; Japan: 2010. http://www.stat.go.jp/english/data/handbook/index.htm. [Google Scholar]
  20. Lang PO, Govind S, Mitchell WA, Siegrist CA, Aspinall R. Vaccine effectiveness in older individuals: What has been learned from the influenza-vaccine experience. Ageing Res Rev. 2010 doi: 10.1016/j.arr.2010.09.005. [DOI] [PubMed] [Google Scholar]
  21. Larbi A, Pawelec G, Wong SC, Goldeck D, Tai JJ, Fulop T. Impact of age on T cell signaling: A general defect or specific alterations? Ageing Res Rev. 2010 doi: 10.1016/j.arr.2010.09.008. [DOI] [PubMed] [Google Scholar]
  22. McCubrey JA, Steelman LS, Abrams SL, Chappell WH, Russo S, Ove R, Milella M, Tafuri A, Lunghi P, Bonati A, Stivala F, Nicoletti F, Libra M, Martelli AM, Montalto G, Cervello M. Emerging MEK inhibitors. Expert Opin Emerg Drugs. 2010;15:203–223. doi: 10.1517/14728210903282760. [DOI] [PubMed] [Google Scholar]
  23. McDade TW. Life history theory and the immune system: steps toward a human ecological immunology. Yearbook Phys Anthropol. 2003;46:100–25. doi: 10.1002/ajpa.10398. [DOI] [PubMed] [Google Scholar]
  24. McElhaney JE. Influenza vaccine responses in older adults. Ageing Res Rev. 2010 doi: 10.1016/j.arr.2010.10.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. McKean KA, Yourth CP, Lazzaro BP, Clark AG. The evolutionary costs of immunological maintenance and deployment. BMC Evol Biol. 2008;8:76. doi: 10.1186/1471-2148-8-76. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Mestas J, Hughes CC. Of mice and not men: differences between mouse and human immunology. J Immunol. 2004;172:2731–2738. doi: 10.4049/jimmunol.172.5.2731. [DOI] [PubMed] [Google Scholar]
  27. NCHS (National Center for Health Statistics) Health United States 2009: With Special Feature on Medical Technology. 2010 DHHS Publication No. 2010-1232. Centers for Disease Control and Prevention, US Department of Health and Human Services, Hyattsville, MD. 574 pp. http://cdc.gov/nchs/data/hus/hus09.pdf#specialfeature. [PubMed]
  28. Parham P, Abi-Rached L, Matevosyan L, Moesta AK, Norman PJ, Older Aguilar AM, Guethlein LA. Primate-specific regulation of natural killer cells. J Med Primatol. 2010;39:194–212. doi: 10.1111/j.1600-0684.2010.00432.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Payne G, Laporte A, Deber R, Coyte PC. Counting backward to health care’s future: using time-to-death modeling to identify changes in end-of-life morbidity and the impact of aging on health care expenditures. Milbank Q. 2007;85:213–257. doi: 10.1111/j.1468-0009.2007.00485.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rice DP, Fineman N. Economic implications of increased longevity in the United States. Annu Rev Public Health. 2004;25:457–473. doi: 10.1146/annurev.publhealth.25.101802.123054. [DOI] [PubMed] [Google Scholar]
  31. Rosenstiel P, Philipp EE, Schreiber S, Bosch TC. Evolution and function of innate immune receptors--insights from marine invertebrates. J Innate Immun. 2009;1:291–300. doi: 10.1159/000211193. [DOI] [PubMed] [Google Scholar]
  32. Rosol TJ, Tannehill-Gregg SH, LeRoy BE, Mandl S, Contag CH. Animal models of bone metastasis. Cancer. 2003;97:S748–S757. doi: 10.1002/cncr.11150. [DOI] [PubMed] [Google Scholar]
  33. Sansoni P, Vescovini R, Fagnoni F, Biasini C, Zanni F, Zanlari L, Telera A, Lucchini G, Passeri G, Monti D, Franceschi C, Passeri M. The immune system in extreme longevity. Exp Gerontol. 2008;43:61–65. doi: 10.1016/j.exger.2007.06.008. [DOI] [PubMed] [Google Scholar]
  34. Shaw AC, Panda A, Joshi SR, Qian F, Allore HG, Montgomery RR. Dysregulation of human Toll-like receptor function in aging. Ageing Res Rev. 2010 doi: 10.1016/j.arr.2010.10.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Stanziano DC, Whitehurst M, Graham P, Roos BA. A review of selected longitudinal studies on aging: past findings and future directions. J Am Geriatr Soc. 2010;58:S292–S297. doi: 10.1111/j.1532-5415.2010.02936.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Shedlock DJ, Silvestri G, Weiner DB. Monkeying around with HIV vaccines: using rhesus macaques to define ‘gatekeepers’ for clinical trials. Nat Rev Immunol. 2009;9:717–728. doi: 10.1038/nri2636. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Singh T, Newman AB. Inflammatory markers in population studies of aging. Ageing Res Rev. 2010 doi: 10.1016/j.arr.2010.11.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. UN-ESA. Demograpic Revolution: The ageing of the world’s population. United Nations Programme on Ageing, Department of Economic and Social Affairs, Population Division. United Nations; New York, NY: 2005. http://www.un.org/ageing/popageing_demo3.html. [Google Scholar]
  39. Vallejo AN. CD28 extinction in human T cells: altered functions and the program of T-cell senescence. Immunol Rev. 2005;205:158–169. doi: 10.1111/j.0105-2896.2005.00256.x. [DOI] [PubMed] [Google Scholar]
  40. Vallejo AN, Mueller RG, Hamel DL, Jr, Way A, Dvergsten JA, Griffin P, Newman AB. Expansions of NK-like αβT cells with chronologic aging: Novel lymphocyte effectors that compensate for functional deficits of conventional NK cells and T cells. Ageing Res Rev. 2010 doi: 10.1016/j.arr.2010.09.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. van Elk R, Mot E, Franses PH. Modeling healthcare expenditures: overview of the literature and evidence from a panel time-series model. Expert Rev Pharmacoecon Outcomes Res. 2010;10:25–35. doi: 10.1586/erp.09.72. [DOI] [PubMed] [Google Scholar]
  42. Wadman M. Funding crisis hits US ageing research. Nature. 2010;468:148. doi: 10.1038/468148a. [DOI] [PubMed] [Google Scholar]
  43. Weill JC, Weller S, Reynaud CA. Human marginal zone B cells. Annu Rev Immunol. 2009;27:267–285. doi: 10.1146/annurev.immunol.021908.132607. [DOI] [PubMed] [Google Scholar]
  44. Wikby A, Ferguson F, Forsey R, Thompson J, Strindhall J, Löfgren S, Nilsson BO, Ernerudh J, Pawelec G, Johansson B. An immune risk phenotype, cognitive impairment, and survival in very late life: impact of allostatic load in Swedish octogenarian and nonagenarian humans. J Gerontol A Biol Sci Med Sci. 2005;60:556–565. doi: 10.1093/gerona/60.5.556. [DOI] [PubMed] [Google Scholar]
  45. Yi KH, Chen L. Fine tuning the immune response through B7-H3 and B7-H4. Immunol Rev. 2009;229:145–151. doi: 10.1111/j.1600-065X.2009.00768.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Zaghouani H, Hoeman CM, Adkins B. Neonatal immunity: faulty T-helpers and the shortcomings of dendritic cells. Trends Immunol. 2009;30:585–591. doi: 10.1016/j.it.2009.09.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Ziegler SF. FOXP3: of mice and men. Annu Rev Immunol. 2006;24:209–226. doi: 10.1146/annurev.immunol.24.021605.090547. [DOI] [PubMed] [Google Scholar]

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