Medical Microbiology and Immunology

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Title CD28 and IL-4: two heavyweights controlling the balance between immunity and inflammation
Author Thomas Hunig, Fred Luhder, Karin Elflein, Tea Gogishvili, Monika Frohlich
Abstract The costimulatory receptor CD28 and IL-4Rα-containing cytokine receptors play key roles in controlling the size and quality of pathogen-specific immune responses. Thus, CD28-mediated costimulation is needed for effective primary T-cell expansion and for the generation and activation of regulatory T-cells (Treg cells), which protect from immunopathology. Similarly, IL-4Rα signals are required for alternative activation of macrophages, which counteract inflammation by type 1 responses. Furthermore, immune modulation by CD28 and IL-4 is interconnected through the promotion of IL-4 producing T-helper 2 cells by CD28 signals. Using conditionally IL-4Rα and CD28 deleting mice, as well as monoclonal antibodies, which block or stimulate CD28, or mAb that deplete Treg cells, we have studied the roles of CD28 and IL-4Rα in experimental mouse models of virus (influenza), intracellular bacteria (L. monocytogenes, M. tuberculosis), and parasite infections (T. congolense, L. major). We observed that in some, but not all settings, Treg cells and type 2 immune deviation, including activation of alternative macrophages can be manipulated to protect the host either from infection or from immunopathology with an overall beneficial outcome. Furthermore, we provide direct evidence that secondary CD8 T-cell responses to i.c. bacteria are dependent on CD28-mediated costimulation.
1. Kelly-Welch AE, Hanson EM, Boothby MR, Keegan AD (2003)
Interleukin-4 and interleukin-13 signaling connections maps.
Science 300(5625):1527–1528
2. Donaldson DD, Whitters MJ, Fitz LJ, Neben TY, Finnerty H,
Henderson SL, O’Hara RM Jr, Beier DR, Turner KJ, Wood CR,
Collins M (1998) The murine IL-13 receptor alpha 2: molecular
cloning, characterization, and comparison with murine IL-13
receptor alpha 1. J Immunol 161(5):2317–2324
3. Fichtner-Feigl S, Strober W, Kawakami K, Puri RK, Kitani A
(2006) IL-13 signaling through the IL-13alpha2 receptor is
involved in induction of TGF-beta1 production and fibrosis. Nat
Med 12(1):99–106
4. Mohrs M, Ledermann B, Kohler G, Dorfmuller A, Gessner A,
Brombacher F (1999) Differences between IL-4- and IL-4
receptor alpha-deficient mice in chronic leishmaniasis reveal a
protective role for IL-13 receptor signaling. J Immunol
5. Brombacher F (2000) The role of interleukin-13 in infectious
diseases and allergy. Bioessays 22(7):646–656
6. Shahinian A, Pfeffer K, Lee KP, Ku¨ndig TM, Kishihara K,
Wakeham A, Kawai K, Ohashi PS, Thompson CB, Mak TW
(1993) Differential T cell costimulatory requirements in CD28-
deficient mice. Science 261:609
7. Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe
A, Bluestone JA (2000) B7/CD28 costimulation is essential for
the homeostasis of the CD4 ? CD25? immunoregulatory T cells
that control autoimmune diabetes. Immunity 12(4):431–440
8. Herbert DR, Holscher C, Mohrs M, Arendse B, Schwegmann A,
Radwanska M, Leeto M, Kirsch R, Hall P, Mossmann H,
Claussen B, Forster I, Brombacher F (2004) Alternative macrophage activation is essential for survival during schistosomiasis
and downmodulates T helper 1 responses and immunopathology.
Immunity 20(5):623–635
9. Horsnell WG, Cutler AJ, Hoving JC, Mearns H, Myburgh E,
Arendse B, Finkelman FD, Owens GK, Erle D, Brombacher F
(2007) Delayed goblet cell hyperplasia, acetylcholine receptor
expression, and worm expulsion in SMC-specific IL-4Ralphadeficient mice. PLoS Pathog 3(1):e1
10. Leeto M, Herbert DR, Marillier R, Schwegmann A, Fick L,
Brombacher F (2006) TH1-dominant granulomatous pathology
does not inhibit fibrosis or cause lethality during murine schistosomiasis. Am J Pathol 169(5):1701–1712
11. Dewals B, Hoving JC, Leeto M, Marillier RG, Govender U,
Cutler AJ, Horsnell WG, Brombacher F (2009) IL-4Ralpha
responsiveness of non-CD4 T cells contributes to resistance in
schistosoma mansoni infection in pan-T cell-specific IL-4Ralphadeficient mice. Am J Pathol 175(2):706–716
12. Dennehy KM, Elias F, Zeder-Lutz G, Ding X, Altschuh D,
Luhder F, Hunig T (2006) Cutting edge: monovalency of CD28
maintains the antigen dependence of T cell costimulatory
responses. J Immunol 176(10):5725–5729
13. Beyersdorf N, Ding X, Blank G, Dennehy KM, Kerkau T, Hunig
T (2008) Protection from graft-versus-host disease with a novel
B7 binding site-specific mouse anti-mouse CD28 monoclonal
antibody. Blood 112(10):4328–4336
14. Gogishvili T, Elias F, Emery JL, McPherson K, Okkenhaug K,
Hunig T, Dennehy KM (2008) Proliferative signals mediated by
CD28 superagonists require the exchange factor Vav1 but not
phosphoinositide 3-kinase in primary peripheral T cells. Eur J
Immunol 38(9):2528–2533
15. Dolfi DV, Katsikis PD (2007) CD28 and CD27 costimulation of
CD8? T cells: a story of survival. Adv Exp Med Biol 590:149–
16. Dooms H, Abbas AK (2006) Control of CD4? T-cell memory by
cytokines and costimulators. Immunol Rev 211:23–38
17. Borowski AB, Boesteanu AC, Mueller YM, Carafides C, Topham
DJ, Altman JD, Jennings SR, Katsikis PD (2007) Memory CD8?
T cells require CD28 costimulation. J Immunol 179(10):6494–
18. Kursar M, Bonhagen K, Fensterle J, Kohler A, Hurwitz R,
Kamradt T, Kaufmann SH, Mittrucker HW (2002) Regulatory
CD4 ? CD25? T cells restrict memory CD8? T cell responses.
J Exp Med 196(12):1585–1592
19. Tacke M, Hanke G, Hanke T, Hunig T (1997) CD28-mediated
induction of proliferation in resting T cells in vitro and in vivo
without engagement of the T cell receptor: evidence for functionally distinct forms of CD28. Eur J Immunol 27(1):239–247
20. Luhder F, Huang Y, Dennehy KM, Guntermann C, Muller I,
Winkler E, Kerkau T, Ikemizu S, Davis SJ, Hanke T, Hunig T
(2003) Topological requirements and signaling properties of T
cell-activating, anti-CD28 antibody superagonists. J Exp Med
21. Evans EJ, Esnouf RM, Manso-Sancho R, Gilbert RJ, James JR,
Yu C, Fennelly JA, Vowles C, Hanke T, Walse B, Hunig T,
Sorensen P, Stuart DI, Davis SJ (2005) Crystal structure of a
soluble CD28-Fab complex. Nat Immunol 6(3):271–279
22. Rodriguez-Palmero M, Hara T, Thumbs A, Hu¨nig T (1999)
Triggering of T-cell proliferation through CD28 induces GATA-3
and promotes T-helper type 2 differentiation in vitro and in vivo.
Eur J Immunol 29:3914–3924
23. Lin C-H, Hunig T (2003) Efficient expansion of regulatory
T-cells in vitro and in vivo with a CD28 superagonist. Eur J
Immunol 33:626–638
24. Gogishvili T, Langenhorst D, Luhder F, Elias F, Elflein K,
Dennehy KM, Gold R, Hunig T (2009) Rapid regulatory T-cell
response prevents cytokine storm in CD28 superagonist treated
mice. PLoS ONE 4(2):e4643
25. Hunig T (2007) Manipulation of regulatory T-cell number and
function with CD28-specific monoclonal antibodies. Adv
Immunol 95:111–148
26. Beaudette-Zlatanova BC, Whalen B, Zipris D, Yagita H, Rozing
J, Groen H, Benjamin CD, Hunig T, Drexhage HA, Ansari MJ,
Leif J, Mordes JP, Greiner DL, Sayegh MH, Rossini AA (2006)
Costimulation and autoimmune diabetes in BB rats. Am J
Transplant 6(5 Pt 1):894–902
27. Beyersdorf N, Gaupp S, Balbach K, Schmidt J, Toyka KV, Lin
CH, Hanke T, Hunig T, Kerkau T, Gold R (2005) Selective targeting of regulatory T cells with CD28 superagonists allows
effective therapy of experimental autoimmune encephalomyelitis.
J Exp Med 202(3):445–455
28. Azuma H, Isaka Y, Li X, Hunig T, Sakamoto T, Nohmi H,
Takabatake Y, Mizui M, Kitazawa Y, Ichimaru N, Ibuki N, Ubai
T, Inamoto T, Katsuoka Y, Takahara S (2008) SuperagonisticCD28 antibody induces donor-specific tolerance in rat renal
allografts. Am J Transplant 8(10):2004–2014
29. Beyersdorf N, Ding X, Hunig T, Kerkau T (2009) Superagonistic
CD28 stimulation of allogeneic T cells protects from acute graftversus-host disease. Blood 114(20):4575–4582
30. Kitazawa Y, Fujino M, Li XK, Xie L, Ichimaru N, Okumi M,
Nonomura N, Tsujimura A, Isaka Y, Kimura H, Hunig T,
Takahara S (2009) Superagonist CD28 antibody preferentially
expanded Foxp3-expressing nTreg cells and prevented graftversus-host diseases. Cell Transplant 18(5):627–637
31. Kitazawa Y, Fujino M, Sakai T, Azuma H, Kimura H, Isaka Y,
Takahara S, Hunig T, Abe R, Li XK (2008) Foxp3-expressing
regulatory T cells expanded with CD28 superagonist antibody
can prevent rat cardiac allograft rejection. J Heart Lung Transplant 27(4):362–371
32. Elflein K, Rodriguez-Palmero M, Kerkau T, Hunig T (2003)
Rapid recovery from T lymphopenia by CD28 superagonist
therapy. Blood 102(5):1764–1770
33. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes
A, Brunner MD, Panoskaltsis N (2006) Cytokine storm in a phase
1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J
Med 355(10):1018–1028
34. Rodriguez-Palmero M, Franch A, Castell M, Pelegri C, PerezCano FJ, Kleinschnitz C, Stoll G, Hunig T, Castellote C (2006)
Effective treatment of adjuvant arthritis with a stimulatory CD28-
specific monoclonal antibody. J Rheumatol 33(1):110–118
35. Guilliams M, Bosschaerts T, Herin M, Hunig T, Loi P, Flamand
V, De Baetselier P, Beschin A (2008) Experimental expansion of
the regulatory T cell population increases resistance to African
trypanosomiasis. J Infect Dis 198(5):781–791
36. Scott P, Natovitz P, Coffman RL, Pearce E, Sher A (1988)
Immunoregulation of cutaneous leishmaniasis. T cell lines that
transfer protective immunity or exacerbation belong to different
T helper subsets and respond to distinct parasite antigens. J Exp
Med 168(5):1675–1684
37. Raes G, De Baetselier P, Noel W, Beschin A, Brombacher F,
Hassanzadeh Gh G (2002) Differential expression of FIZZ1 and
Ym1 in alternatively versus classically activated macrophages. J
Leukoc Biol 71(4):597–602
38. Mountford AP, Hogg KG, Coulson PS, Brombacher F (2001)
Signaling via interleukin-4 receptor alpha chain is required for
successful vaccination against schistosomiasis in BALB/c mice.
Infect Immun 69(1):228–236
39. Raes G, Brys L, Dahal BK, Brandt J, Grooten J, Brombacher F,
Vanham G, Noel W, Bogaert P, Boonefaes T, Kindt A, Van den
Bergh R, Leenen PJ, De Baetselier P, Ghassabeh GH (2005)
Macrophage galactose-type C-type lectins as novel markers for
alternatively activated macrophages elicited by parasitic infections and allergic airway inflammation. J Leukoc Biol 77(3):321–
40. Linehan SA, Coulson PS, Wilson RA, Mountford AP, Brombacher F, Martinez-Pomares L, Gordon S (2003) IL-4 receptor
signaling is required for mannose receptor expression by macrophages recruited to granulomata but not resident cells in mice
infected with Schistosoma mansoni. Lab Invest 83(8):1223–1231
41. Noel W, Hassanzadeh G, Raes G, Namangala B, Daems I, Brys
L, Brombacher F, Baetselier PD, Beschin A (2002) Infection
stage-dependent modulation of macrophage activation in trypanosoma congolense-resistant and -susceptible mice. Infect
Immun 70(11):6180–6187
42. Ghassabeh GH, De Baetselier P, Brys L, Noel W, Van Ginderachter JA, Meerschaut S, Beschin A, Brombacher F, Raes G
(2006) Identification of a common gene signature for type II
cytokine-associated myeloid cells elicited in vivo in different
pathologic conditions. Blood 108(2):575–583
43. Ho¨lscher C, Arendse B, Schwegmann A, Myburgh E, Brombacher F (2005) Impairment of alternative macrophage activation
delays cutaneous leishmaniasis in non-healing BALB/c mice. J
Immunol 176:1115–1121
44. Muller U, Stenzel W, Kohler G, Werner C, Polte T, Hansen G,
Schutze N, Straubinger RK, Blessing M, McKenzie AN,
Brombacher F, Alber G (2007) IL-13 induces disease-promoting
type 2 cytokines, alternatively activated macrophages and allergic
inflammation during pulmonary infection of mice with Cryptococcus neoformans. J Immunol 179(8):5367–5377
45. Stenzel W, Muller U, Kohler G, Heppner FL, Blessing M,
McKenzie AN, Brombacher F, Alber G (2009) IL-4/IL-13-
dependent alternative activation of macrophages but not microglial cells is associated with uncontrolled cerebral cryptococcosis. Am J Pathol 174(2):486–496
46. Cao Y, Brombacher F, Tunyogi-Csapo M, Glant TT, Finnegan A
(2007) Interleukin-4 regulates proteoglycan-induced arthritis by
specifically suppressing the innate immune response. Arthritis
Rheum 56(3):861–870
47. Keating P, O’Sullivan D, Tierney JB, Kenwright D, Miromoeini
S, Mawasse L, Brombacher F, La Flamme AC (2009) Protection
from EAE by IL-4Ralpha(-/-) macrophages depends upon T
regulatory cell involvement. Immunol Cell Biol 87(7):534–545
48. Brys L, Beschin A, Raes G, Ghassabeh GH, Noel W, Brandt J,
Brombacher F, De Baetselier P (2005) Reactive oxygen species
and 12/15-lipoxygenase contribute to the antiproliferative
capacity of alternatively activated myeloid cells elicited during
helminth infection. J Immunol 174(10):6095–6104
49. Pesce JT, Ramalingam TR, Wilson MS, Mentink-Kane MM,
Thompson RW, Cheever AW, Urban JF Jr, Wynn TA (2009)
Retnla (relmalpha/fizz1) suppresses helminth-induced Th2-type
immunity. PLoS Pathog 5(4):e1000393
50. Barner M, Mohrs M, Brombacher F, Kopf M (1998) Differences
between IL-4R alpha-deficient and IL-4-deficient mice reveal a
role for IL-13 in the regulation of Th2 responses. Curr Biol
51. Marillier RG, Michels C, Smith EM, Fick LC, Leeto M, Dewals
B, Horsnell WG, Brombacher F (2008) IL-4/IL-13 independent
goblet cell hyperplasia in experimental helminth infections. BMC
Immunol 9:11
52. Radwanska M, Cutler AJ, Hoving JC, Magez S, Holscher C,
Bohms A, Arendse B, Kirsch R, Hunig T, Alexander J, Kaye P,
Brombacher F (2007) Deletion of IL-4Ralpha on CD4 T cells
renders BALB/c mice resistant to Leishmania major infection.
PLoS Pathog 3(5):e68
Keywords CD28 - Costimulation - IL-4 - IL-4R - Alternatively activated macrophages - Mouse models - Conditional knockout - Monoclonal antibodies - Regulatory T-cells - Influenza - L. monocytogenes - M. tuberculosis - T. congolense - L. major
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