The potential role of T-cells and their interaction with antigen-presenting cells in mediating immunosuppression following trauma-hemorrhage

Abstract

Objective: Trauma-hemorrhage results in depressed immune responses of antigen-presenting cells (APCs) and T-cells. Recent studies suggest a key role of depressed T-cell derived interferon (IFN)-g in this complex immune cell interaction. The aim of this study was to elucidate further the underlying mechanisms responsible for dysfunctional T-cells and their interaction with APCs following trauma-hemorrhage.

Design: Adult C3H/HeN male mice were subjected to trauma-hemorrhage (3-cm midline laparotomy) followed by hemorrhage (blood pressure of 35 ± 5 mmHg for 90 min and resuscitation) or sham operation. At 24 h thereafter, spleens were harvested and T-cells (by Microbeads) and APCs (via adherence) were Isolated. Co-cultures of T-cells and APCs were established for 48 h and stimulated with concanavalin A and lipopolysaccharide. T-Cell specific cytokines known to affect APC function (i.e. interleukin(IL)-2, IL-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF)) were measured in culture supernatants by Multiplex assay. The expression of MHC class II as well as co-stimulatory surface molecules on T-cells and APCs was determined by flow cytometry.

Results: The release of IL-4 and GM-CSF by T-cells was suppressed following trauma-hemorrhage, irrespective of whether sham or trauma-hemorrhage APCs were present. Antigen-presenting cells from animals subjected to trauma-hemorrhage did not affect T-cell derived cytokine release by sham T-cells. In contrast, T-cells from trauma-hemorrhage animals depressed MHC class II expression of CD11c(+) cells, irrespective of whether APCs underwent sham or trauma-hemorrhage procedure. Surprisingly, co-stimulatory molecules on APCs (CD80, CD86) were not affected by trauma-hemorrhage.

Conclusions: These results suggest that beside IFN-g other T-cell derived cytokines contribute to immunosuppression following trauma-hemorrhage causing diminished MHC II expression on APCs. Thus, T-cells appear to play an important role in this interaction at the time-point examined. Therapeutic approaches should aim at maintenance of T-cell function and their interaction with APCs to prevent extended immunosuppression following trauma-hemorrhage.

Keywords

Antigen-presenting cells dendritic cells MHC class II cytokines co-stimulatory molecules

References

Angele MK , Chaudry IH Surgical trauma and immunosuppression: pathophysiology and potential immunomodulatory approaches. Langenbecks Arch Surg 2005; 390: 333-341.

Walz CR , Zedler S. , Schneider CP et al. Depressed T cell-derived IFN-gamma following trauma-hemorrhage: a potential mechanism for diminished APC responses. Langenbecks Arch Surg 2007; 392: 339-343.

Lenschow DJ , Walunas TL , Bluestone JA CD28/B7 system of T cell costimulation. Annu Rev Immunol 1996; 14: 233-258.

Ayala A. , Ertel W. , Chaudry IH Trauma-induced suppression of antigen presentation and expression of major histocompatibility class II antigen complex in leukocytes. Shock 1996; 5: 79-90.

Angele MK , Knoferl MW , Schwacha MG et al. Sex steroids regulate pro- and anti-inflammatory cytokine release by macrophages after trauma-hemorrhage. Am J Physiol 1999; 277: C35-C42.

Angele MK , Knoferl MW , Ayala A. , Bland KI , Chaudry IH Testosterone and estrogen differently effect Th1 and Th2 cytokine release following trauma-hemorrhage. Cytokine 2001 ; 16: 22-30.

Xu YX , Ayala A. , Chaudry IH Prolonged immunodepression after trauma and hemorrhagic shock. J Trauma 1998; 44: 335-341.

Ertel W. , Keel M. , Neidhardt R. et al. Inhibition of the defense system stimulating interleukin-12 interferon-gamma pathway during critical illness. Blood 1997; 89: 1612-1620.

Kawasaki T. , Fujimi S. , Lederer JA et al. Trauma-hemorrhage induces depressed splenic dendritic cell functions in mice. J Immunol 2006; 177: 4514-4520.

10.

Angele MK , Faist E. Clinical review: immunodepression in the surgical patient and increased susceptibility to infection. Crit Care 2002; 6: 298-305.

11.

Angele MK , Schwacha MG , Ayala A. , Chaudry IH Effect of gender and sex hormones on immune responses following shock. Shock 2000; 14: 81-90.

12.

Zellweger R. , Ayala A. , DeMaso CM , Chaudry IH Trauma-hemorrhage causes prolonged depression in cellular immunity. Shock 1995; 4: 149-153.

13.

Angele MK , Ayala A. , Cioffi WG , Bland KI , Chaudry IH Testosterone: the culprit for producing splenocyte immune depression after trauma hemorrhage. Am J Physiol 1998; 274: C1530-C1536.

14.

Delon J. , Stoll S. , Germain RN Imaging of T-cell interactions with antigen presenting cells in culture and in intact lymphoid tissue. Immunol Rev 2002 ; 189: 51-63.

15.

Vendetti S. , Chai JG , Dyson J. , Simpson E. , Lombardi G. , Lechler R. Anergic T cells inhibit the antigen-presenting function of dendritic cells. J Immunol 2000 ; 165: 1175-1181.

16.

Gregg EO , Denis M. The effect of macrophage activation state on antigen presenting capability as defined by helper T-cell function. Int J Immunopharmacol 1991; 13: 217-225.

17.

Ayala A. , Perrin MM , Wagner MA , Chaudry IH Enhanced susceptibility to sepsis after simple hemorrhage. Depression of Fc and C3b receptor-mediated phagocytosis. Arch Surg 1990; 125: 70-74, discussion 74-75.

18.

Partington KM , Jenkinson EJ , Anderson G. A novel method of cell separation based on dual parameter immunomagnetic cell selection. J Immunol Methods 1999; 223: 195-205.

19.

Abraham E. T- and B-cell function and their roles in resistance to infection. New Horiz 1993; 1: 28-36.

20.

Ayala A. , Chung CS , Xu YX , Evans TA , Redmond KM , Chaudry IH Increased inducible apoptosis in CD4+ T lymphocytes during polymicrobial sepsis is mediated by Fas ligand and not endotoxin. Immunology 1999; 97: 45-55.

21.

Shelley O. , Murphy T. , Paterson H. , Mannick JA , Lederer JA Interaction between the innate and adaptive immune systems is required to survive sepsis and control inflammation after injury. Shock 2003; 20: 123-129.

22.

Landy M. , Baker PJ Cytodynamics of the distinctive immune response produced in regional lymph nodes by Salmonella somatic polysaccharide. J Immunol 1966; 97: 670-679.

23.

Berger SL Lymphocytes as resting cells. Methods Enzymol 1975; 58: 486-494.

24.

Bryn T. , Yaqub S. , Mahic M. , Henjum K. , Aandahl EM , Tasken K. LPS-activated monocytes suppress T-cell immune responses and induce FOXP3+ T cells through a COX-2-PGE2-dependent mechanism. Int Immunol 2008; 20: 235-245.

25.

Ransom J. , Fischer M. , Mosmann T. et al. Interferon-gamma is produced by activated immature mouse thymocytes and inhibits the interleukin 4-induced proliferation of immature thymocytes . J Immunol 1987; 139: 4102-4108.

26.

de Saint-Vis B. , Fugier-Vivier I. , Massacrier C. et al. The cytokine profile expressed by human dendritic cells is dependent on cell subtype and mode of activation. J Immunol 1998; 160: 1666-1676.

27.

Ayala A. , Deol ZK , Lehman DL , Herdon CD , Chaudry IH Polymicrobial sepsis but not low-dose endotoxin infusion causes decreased splenocyte IL-2/IFN-gamma release while increasing IL-4/IL-10 production. J Surg Res 1994; 56: 579-585.

28.

Schinkel C. The role of IFN-gamma in surgical patients. J Interferon Cytokine Res 2003; 23: 341-349.

29.

Asthana D. , Yang WC , Fuller L. et al. Differential effects of IFN-gamma on kidney cell expression of MHC class II molecules, kidney cell associated molecules and their stimulatory capacity in mixed lymphocyte kidney cell culture. Transpl Immunol 1993; 1: 282-293.

30.

Granucci F. , Zanoni I. , Feau S. , Ricciardi-Castagnoli P. Dendritic cell regulation of immune responses: a new role for interleukin 2 at the intersection of innate and adaptive immunity. EMBO J 2003; 22: 2546-2551.

31.

De AK , Laudanski K. , Miller-Graziano CL Failure of monocytes of trauma patients to convert to immature dendritic cells is related to preferential macrophage-colony-stimulating factor-driven macrophage differentiation. J Immunol 2003; 170: 6355-6362.

32.

Banchereau J. , Steinman RM Dendritic cells and the control of immunity . Nature 1998; 392: 245-252.

33.

Schneider CP , Schwacha MG , Chaudry IH Influence of gender and age on T-cell responses in a murine model of trauma-hemorrhage: differences between circulating and tissue-fixed cells. J Appl Physiol 2006; 100: 826-833.

34.

Oberbeck R. , Nickel E. , von Griensven M. et al. The effect of dehydroepiandrosterone on hemorrhage-induced suppression of cellular immune function. Intensive Care Med 2002; 28: 963-968.

35.

Sun ZW , Qiu YH , Shi YJ et al. Time courses of B7 family molecules expressed on activated T-cells and their biological significance. Cell Immunol 2005; 236: 146-153.

36.

Turina M. , Dickinson A. , Gardner S. , Polk Jr HC Monocyte HLA-DR and interferon-gamma treatment in severely injured patients - a critical reappraisal more than a decade later. J Am Coll Surg 2006; 203: 73-81.