Immune Netw.  2016 Dec;16(6):322-329. 10.4110/in.2016.16.6.322.

Unusual CD4⁺CD28⁻ T Cells and Their Pathogenic Role in Chronic Inflammatory Disorders

• Lee GH
• Lee WW

• KMID: 2362796
• DOI: http://doi.org/10.4110/in.2016.16.6.322

Abstract

CD28 is a primary co-stimulatory receptor that is essential for successful T cell activation, proliferation, and survival. While ubiquitously expressed on naive T cells, the level of CD28 expression on memory T cells is largely dependent on the T-cell differentiation stage in humans. Expansion of circulating T cells lacking CD28 was originally considered a hallmark of age-associated immunological changes in humans, with a progressive loss of CD28 following replicative senescence with advancing age. However, an increasing body of evidence has revealed that there is a significant age-inappropriate expansion of CD4⁺CD28⁻ T cells in patients with a variety of chronic inflammatory diseases, suggesting that these cells play a role in their pathogenesis. In fact, expanded CD4⁺CD28⁻ T cells can produce large amounts of proinflammatory cytokines such as IFN-γ and TNF-α and also have cytotoxic potential, which may cause tissue damage and development of pathogenesis in many inflammatory disorders. Here we review the characteristics of CD4⁺CD28⁻ T cells as well as the recent advances highlighting the contribution of these cells to several disease conditions.

Keyword

CD28; Co-stimulatory receptor; CD4⁺CD28⁻ T cells; Chronic inflammatory diseases; Cytotoxic potential

MeSH Terms

Cell Aging
Cytokines
Humans
Memory
T-Lymphocytes*
Cytokines

Figure

• 

  Figure 1 Immunological role of expanded CD4+CD28− T cells in chronic inflammatory disorders. CD28+ T cells lose CD28 expression after repeated stimulation with latent viral infections or autoantigen. Additionally, the loss of CD28 occurs when T cells are exposed to proinflammatory cytokines. Expanded CD4+CD28− T cells produce large amounts of proinflammatory cytokines (e.g. IFN-γ and TNF-α) and cytotoxic mediators (e.g. granzyme B and perforin), which cause tissue damage and development of pathogenesis in many inflammatory disorders such as RA, cardiovascular diseases and chronic graft rejection of solid organ transplantation.

Reference

1. Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations (^*). Annu Rev Immunol. 2010; 28:445–489.

2. Lafferty KJ, Cunningham AJ. A new analysis of allogeneic interactions. Aust J Exp Biol Med Sci. 1975; 53:27–42.

3. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013; 13:227–242.

4. Acuto O, Michel F. CD28-mediated co-stimulation: a quantitative support for TCR signalling. Nat Rev Immunol. 2003; 3:939–951.

5. Appay V, van Lier RA, Sallusto F, Roederer M. Phenotype and function of human T lymphocyte subsets: consensus and issues. Cytometry A. 2008; 73:975–983.

6. Derhovanessian E, Maier AB, Hahnel K, Beck R, de Craen AJ, Slagboom EP, Westendorp RG, Pawelec G. Infection with cytomegalovirus but not herpes simplex virus induces the accumulation of late-differentiated CD4⁺ and CD8⁺ T-cells in humans. J Gen Virol. 2011; 92:2746–2756.

7. Weng NP, Akbar AN, Goronzy J. CD28(−) T cells: their role in the age-associated decline of immune function. Trends Immunol. 2009; 30:306–312.

8. Vallejo AN, Bryl E, Klarskov K, Naylor S, Weyand CM, Goronzy JJ. Molecular basis for the loss of CD28 expression in senescent T cells. J Biol Chem. 2002; 277:46940–46949.

9. Czesnikiewicz-Guzik M, Lee WW, Cui D, Hiruma Y, Lamar DL, Yang ZZ, Ouslander JG, Weyand CM, Goronzy JJ. T cell subset-specific susceptibility to aging. Clin Immunol. 2008; 127:107–118.

10. Yu HT, Park S, Shin EC, Lee WW. T cell senescence and cardiovascular diseases. Clin Exp Med. 2016; 16:257–263.

11. Broux B, Markovic-Plese S, Stinissen P, Hellings N. Pathogenic features of CD4⁺. Trends Mol Med. 2012; 18:446–453.

12. Schmidt D, Goronzy JJ, Weyand CM. CD4⁺ CD7⁻. J Clin Invest. 1996; 97:2027–2037.

13. Liuzzo G, Kopecky SL, Frye RL, O'Fallon WM, Maseri A, Goronzy JJ, Weyand CM. Perturbation of the T-cell repertoire in patients with unstable angina. Circulation. 1999; 100:2135–2139.

14. Betjes MG, Huisman M, Weimar W, Litjens NH. Expansion of cytolytic CD4⁺. Kidney Int. 2008; 74:760–767.

15. Dumitriu IE, Araguas ET, Baboonian C, Kaski JC. CD4⁺ CD28 null T cells in coronary artery disease: when helpers become killers. Cardiovasc Res. 2009; 81:11–19.

16. Fann M, Chiu WK, Wood WH III, Levine BL, Becker KG, Weng NP. Gene expression characteristics of CD28null memory phenotype CD8⁺ T cells and its implication in T-cell aging. Immunol Rev. 2005; 205:190–206.

17. Valenzuela HF, Effros RB. Divergent telomerase and CD28 expression patterns in human CD4 and CD8 T cells following repeated encounters with the same antigenic stimulus. Clin Immunol. 2002; 105:117–125.

18. Chiu WK, Fann M, Weng NP. Generation and growth of CD28nullCD8⁺ memory T cells mediated by IL-15 and its induced cytokines. J Immunol. 2006; 177:7802–7810.

19. Borthwick NJ, Lowdell M, Salmon M, Akbar AN. Loss of CD28 expression on CD8(+) T cells is induced by IL-2 receptor gamma chain signalling cytokines and type I IFN, and increases susceptibility to activation-induced apoptosis. Int Immunol. 2000; 12:1005–1013.

20. Bryl E, Vallejo AN, Weyand CM, Goronzy JJ. Down-regulation of CD28 expression by TNF-alpha. J Immunol. 2001; 167:3231–3238.

21. Liaskou E, Jeffery LE, Trivedi PJ, Reynolds GM, Suresh S, Bruns T, Adams DH, Sansom DM, Hirschfield GM. Loss of CD28 expression by liver-infiltrating T cells contributes to pathogenesis of primary sclerosing cholangitis. Gastroenterology. 2014; 147:221–232.

22. Vallejo AN, Weyand CM, Goronzy JJ. Functional disruption of the CD28 gene transcriptional initiator in senescent T cells. J Biol Chem. 2001; 276:2565–2570.

23. Vallejo AN. CD28 extinction in human T cells: altered functions and the program of T-cell senescence. Immunol Rev. 2005; 205:158–169.

24. Cavanagh MM, Weyand CM, Goronzy JJ. Chronic inflammation and aging: DNA damage tips the balance. Curr Opin Immunol. 2012; 24:488–493.

25. Shaw AC, Joshi S, Greenwood H, Panda A, Lord JM. Aging of the innate immune system. Curr Opin Immunol. 2010; 22:507–513.

26. Franceschi C, Bonafe M, Valensin S, Olivieri F, De LM, Ottaviani E, De BG. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000; 908:244–254.

27. Ortiz-Suarez A, Miller RA. A subset of CD8 memory T cells from old mice have high levels of CD28 and produce IFN-gamma. Clin Immunol. 2002; 104:282–292.

28. Pitcher CJ, Hagen SI, Walker JM, Lum R, Mitchell BL, Maino VC, Axthelm MK, Picker LJ. Development and homeostasis of T cell memory in rhesus macaque. J Immunol. 2002; 168:29–43.

29. Mestas J, Hughes CC. Of mice and not men: differences between mouse and human immunology. J Immunol. 2004; 172:2731–2738.

30. Kipling D, Cooke HJ. Hypervariable ultra-long telomeres in mice. Nature. 1990; 347:400–402.

31. High KP, Akbar AN, Nikolich-Zugich J. Translational research in immune senescence: assessing the relevance of current models. Semin Immunol. 2012; 24:373–382.

32. Weyand CM, Brandes JC, Schmidt D, Fulbright JW, Goronzy JJ. Functional properties of CD4⁺. Mech Ageing Dev. 1998; 102:131–147.

33. Dumitriu IE, Baruah P, Finlayson CJ, Loftus IM, RF Antunes, Lim P, Bunce N, Kaski JC. High levels of costimulatory receptors OX40 and 4-1BB characterize CD4⁺CD28null T cells in patients with acute coronary syndrome. Circ Res. 2012; 110:857–869.

34. Chanouzas D, Dyall L, Dale J, Moss P, Morgan M, Harper L. CD4⁺. Lancet. 2015; 385:Suppl 1. S30.

35. Dumitriu IE. The life (and death) of CD4⁺ CD28(null) T cells in inflammatory diseases. Immunology. 2015; 146:185–193.

36. Maly K, Schirmer M. The story of CD4⁺. J Immunol Res. 2015; 2015:348746.

37. Groh V, Bruhl A, El-Gabalawy H, Nelson JL, Spies T. Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis. Proc Natl Acad Sci U S A. 2003; 100:9452–9457.

38. Namekawa T, Snyder MR, Yen JH, Goehring BE, Leibson PJ, Weyand CM, Goronzy JJ. Killer cell activating receptors function as costimulatory molecules on CD4⁺CD28null T cells clonally expanded in rheumatoid arthritis. J Immunol. 2000; 165:1138–1145.

39. Yen JH, Moore BE, Nakajima T, Scholl D, Schaid DJ, Weyand CM, Goronzy JJ. Major histocompatibility complex class I-recognizing receptors are disease risk genes in rheumatoid arthritis. J Exp Med. 2001; 193:1159–1167.

40. Lee WW, Yang ZZ, Li G, Weyand CM, Goronzy JJ. Unchecked CD70 expression on T cells lowers threshold for T cell activation in rheumatoid arthritis. J Immunol. 2007; 179:2609–2615.

41. Di Mitri D, Azevedo RI, Henson SM, Libri V, Riddell NE, Macaulay R, Kipling D, Soares MV, Battistini L, Akbar AN. Reversible senescence in human CD4⁺CD45RA⁺. J Immunol. 2011; 187:2093–2100.

42. Lanna A, Henson SM, Escors D, Akbar AN. The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells. Nat Immunol. 2014; 15:965–972.

43. Fasth AE, Snir O, Johansson AA, Nordmark B, Rahbar A, Af KE, Bjorkstrom NK, Ulfgren AK, van Vollenhoven RF, Malmstrom V, Trollmo C. Skewed distribution of proinflammatory CD4⁺CD28null T cells in rheumatoid arthritis. Arthritis Res Ther. 2007; 9:R87.

44. McInnes IB, O'Dell JR. State-of-the-art: rheumatoid arthritis. Ann Rheum Dis. 2010; 69:1898–1906.

45. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011; 365:2205–2219.

46. Martens PB, Goronzy JJ, Schaid D, Weyand CM. Expansion of unusual CD4⁺ T cells in severe rheumatoid arthritis. Arthritis Rheum. 1997; 40:1106–1114.

47. Namekawa T, Wagner UG, Goronzy JJ, Weyand CM. Functional subsets of CD4 T cells in rheumatoid synovitis. Arthritis Rheum. 1998; 41:2108–2116.

48. Schirmer M, Vallejo AN, Weyand CM, Goronzy JJ. Resistance to apoptosis and elevated expression of Bcl-2 in clonally expanded CD4⁺. J Immunol. 1998; 161:1018–1025.

49. Vallejo AN, Schirmer M, Weyand CM, Goronzy JJ. Clonality and longevity of CD4⁺CD28null T cells are associated with defects in apoptotic pathways. J Immunol. 2000; 165:6301–6307.

50. Warrington KJ, Takemura S, Goronzy JJ, Weyand CM. CD4⁺. Arthritis Rheum. 2001; 44:13–20.

51. Thewissen M, Somers V, Hellings N, Fraussen J, Damoiseaux J, Stinissen P. CD4+CD28null T cells in autoimmune disease: pathogenic features and decreased susceptibility to immunoregulation. J Immunol. 2007; 179:6514–6523.

52. Zal B, Kaski JC, Arno G, Akiyu JP, Xu Q, Cole D, Whelan M, Russell N, Madrigal JA, Dodi IA, Baboonian C. Heat-shock protein 60-reactive CD4⁺CD28null T cells in patients with acute coronary syndromes. Circulation. 2004; 109:1230–1235.

53. Alonso-Arias R, Moro-Garcia MA, Vidal-Castineira JR, Solano-Jaurrieta JJ, Suarez-Garcia FM, Coto E, Lopez-Larrea C. IL-15 preferentially enhances functional properties and antigen-specific responses of CD4⁺CD28(null) compared to CD4⁺CD28⁺ T cells. Aging Cell. 2011; 10:844–852.

54. Broux B, Mizee MR, Vanheusden M, van der PS, van HJ, Van WB, Somers V, de Vries HE, Stinissen P, Hellings N. IL-15 amplifies the pathogenic properties of CD4⁺. J Immunol. 2015; 194:2099–2109.

55. Goronzy JJ, Weyand CM. T-cell co-stimulatory pathways in autoimmunity. Arthritis Res Ther. 2008; 10:Suppl 1. S3.

56. Fasth AE, Bjorkstrom NK, Anthoni M, Malmberg KJ, Malmstrom V. Activating NK-cell receptors co-stimulate CD4(+)CD28(−) T cells in patients with rheumatoid arthritis. Eur J Immunol. 2010; 40:378–387.

57. Goronzy JJ, Henel G, Sawai H, Singh K, Lee EB, Pryshchep S, Weyand CM. Costimulatory pathways in rheumatoid synovitis and T-cell senescence. Ann N Y Acad Sci. 2005; 1062:182–194.

58. Sawai H, Park YW, Roberson J, Imai T, Goronzy JJ, Weyand CM. T cell costimulation by fractalkine-expressing synoviocytes in rheumatoid arthritis. Arthritis Rheum. 2005; 52:1392–1401.

59. Leon ML, Zuckerman SH. Gamma interferon: a central mediator in atherosclerosis. Inflamm Res. 2005; 54:395–411.

60. Nakajima T, Schulte S, Warrington KJ, Kopecky SL, Frye RL, Goronzy JJ, Weyand CM. T-cell-mediated lysis of endothelial cells in acute coronary syndromes. Circulation. 2002; 105:570–575.

61. Liuzzo G, Goronzy JJ, Yang H, Kopecky SL, Holmes DR, Frye RL, Weyand CM. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. Circulation. 2000; 101:2883–2888.

62. Liuzzo G, Biasucci LM, Trotta G, Brugaletta S, Pinnelli M, Digianuario G, Rizzello V, Rebuzzi AG, Rumi C, Maseri A, Crea F. Unusual CD4⁺CD28null T lymphocytes and recurrence of acute coronary events. J Am Coll Cardiol. 2007; 50:1450–1458.

63. Brugaletta S, Biasucci LM, Pinnelli M, Biondi-Zoccai G, Di GG, Trotta G, Liuzzo G, Crea F. Novel anti-inflammatory effect of statins: reduction of CD4⁺CD28null T lymphocyte frequency in patients with unstable angina. Heart. 2006; 92:249–250.

64. Betjes MG. Immune cell dysfunction and inflammation in end-stage renal disease. Nat Rev Nephrol. 2013; 9:255–265.

65. Betjes MG, Weimar W, Litjens NH. Circulating CD4(+)CD28null T Cells May Increase the risk of an atherosclerotic vascular event shortly after kidney transplantation. J Transplant. 2013; 2013:841430.

66. Brando B, Sommaruga E, Civati G, Busnach G, Broggi ML, Seveso M, Minetti L. Monitoring of CD4⁺. Transplant Proc. 1989; 21:1192–1193.

67. Pawlik A, Florczak M, Masiuk M, Dutkiewicz G, Machalinski B, Rozanski J, Domanski L, Gawronska-Szklarz B. The expansion of CD4⁺. Transplant Proc. 2003; 35:2902–2904.

68. Pawlik A, Florczak M, Masiuk M, Machalinski B, Syczewska M, Szych Z, Gawronska-Szklarz B. The increased number of CD4⁺. Ann Transplant. 2003; 8:54–56.

69. Pearl JP, Parris J, Hale DA, Hoffmann SC, Bernstein WB, McCoy KL, Swanson SJ, Mannon RB, Roederer M, Kirk AD. Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following antibody-mediated T-cell depletion. Am J Transplant. 2005; 5:465–474.

70. Trzonkowski P, Zilvetti M, Friend P, Wood KJ. Recipient memory-like lymphocytes remain unresponsive to graft antigens after CAMPATH-1H induction with reduced maintenance immunosuppression. Transplantation. 2006; 82:1342–1351.

71. Espinosa J, Herr F, Tharp G, Bosinger S, Song M, Farris AB III, George R, Cheeseman J, Stempora L, Townsend R, Durrbach A, Kirk AD. CD57(+) CD4 T Cells Underlie Belatacept-Resistant Allograft Rejection. Am J Transplant. 2016; 16:1102–1112.

72. Shabir S, Smith H, Kaul B, Pachnio A, Jham S, Kuravi S, Ball S, Chand S, Moss P, Harper L, Borrows R. Cytomegalovirus-Associated CD4(+) CD28(null) Cells in NKG2D-Dependent Glomerular Endothelial Injury and Kidney Allograft Dysfunction. Am J Transplant. 2016; 16:1113–1128.

73. Mou D, Espinosa J, Lo DJ, Kirk AD. CD28 negative T cells: is their loss our gain? Am J Transplant. 2014; 14:2460–2466.

74. Murakami N, Riella LV. CD4⁺ CD28-Negative Cells: Armed and Dangerous. Am J Transplant. 2016; 16:1045–1046.