Induction of global anergy rather than inhibitory Th2 lymphokines mediates posttrauma T cell immunodepression.
Depressed mitogen-induced IL-2 and IFN-gamma responses after severe mechanical or thermal injury are postulated to result from an expansion of Th2 lymphocytes with concomitant excessive production of IL-4 and/or IL-10. Here, we simultaneously assessed proliferation and Th1 (IFN-gamma) versus Th2 (IL-10, IL-4) lymphokine production in trauma patients' isolated T cells stimulated in a costimulation sufficient, antigen presenting cell independent system (anti CD3 + anti-CD4). T cells with depressed proliferation and IL-2 production simultaneously lost IL-4, IL-10, and IFN-gamma protein and mRNA responses. Exogenous IL-12 addition did not restore IFNgamma responses, but exogenous IL-2 partially restored IL-4, IFN-gamma, and IL-10 production. Although initially partially restored by exogenous IL-2 or stimulation with PMA + ionomycin, patient T cells with persisting anergy progressively lost even these lymphokine and proliferative responses. Development of global T cell anergy was not a result of lost T cell viability or protein synthesis, since it corresponded to predominance of anergic T cells with upregulated expression of CD11b, but downregulated CD28 and CD3 expression. Thus, the subset of posttrauma patients whose isolated T cells become unresponsive experienced progressively worsening global anergy, mediated not by an increased production of Th2 lymphokines, but possibly by T cell incapacity to be activated through TCR triggering or Ca(2+) mobilization.
De
A K
AK
Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
Kodys
K M
KM
Pellegrini
J
J
Yeh
B
B
Furse
R K
RK
Bankey
P
P
Miller-Graziano
C L
CL
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002056:Burns / Q000276:immunology*; D018106:CD28 Antigens / Q000096:biosynthesis; D002455:Cell Division; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics; D016177:Macrophage-1 Antigen / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000235:genetics; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology*; D014947:Wounds and Injuries / Q000276:immunology*
D018106:CD28 Antigens; D007376:Interleukin-2; D016177:Macrophage-1 Antigen; D012333:RNA, Messenger; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma