In vivo depletion of CD8+ T cells results in Th2 cytokine production and alternate mechanisms of allograft rejection

Sherri Y. Chan, Lisa A. DeBruyne, Richard E. Goodman, Ernst J. Eichwald, D. Keith Bishop

Research output: Contribution to journalArticle

160 Citations (Scopus)

Abstract

A current hypothesis states that Th1 cytokines promote allograft rejection and that Th2 cytokines promote graft acceptance. We present data that question the tolerogenic activity of Th2 cytokines, and we suggest that Th2 cytokines may evoke allograft rejection by recruitment of alternate effector mechanisms. Unmodified rejection of mouse heterotopic cardiac allografts is associated with the accumulation of large numbers of donor-reactive CD8+ CTL within the allograft, which is indicative of a Thl-driven cellular response. However, when recipients are depleted of CD8+ CTL, rejection still occurs and is associated with an aggressive cellular infiltrate rich in eosinophils, large mononuclear cells, and fibroblast-like cells. Eosinophils, which are responsive to the Th2 cytokines IL-4 and IL-5, are not present in unmodified rejecting allografts. Differential production of Thl versus Th2 cytokines was further suggested by altered levels of IgG2a (promoted by IFNγ) and IgGl (promoted by IL-4) alloantibody in the sera of these mice; IgG2a dominated the alloantibody response in unmodified allograft recipients, whereas IgG1 levels increased in recipients depleted of CD8+ CTL. Altered intragraft cytokine gene expression was verified by RT-PCR; Thl (IL-2, IFNγ), but not Th2 (IL-4, IL-5, IL-10), cytokine mRNAs were readily detectable in the allografts of unmodified recipients. In contrast, both Thl and Th2 cytokine genes were expressed in the allografts of mice depleted of CD8+ CTL. These data suggest that donor-reactive CD8+ CTL inhibit intragraft production of Th2 cytokines, thereby promoting a Thl domi-nated-rejection response. Elimination of CD8+ cells allows Th2 cytokine production, which may have deleterious, rather than protective, effects.

Original languageEnglish (US)
Pages (from-to)1155-1161
Number of pages7
JournalTransplantation
Volume59
Issue number8
DOIs
StatePublished - Apr 27 1995

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Allografts
Cytokines
T-Lymphocytes
Interleukin-4
Isoantibodies
Interleukin-5
Eosinophils
Th2 Cells
Interleukin-10
Interleukin-2
Fibroblasts
Immunoglobulin G
Transplants
Gene Expression
Polymerase Chain Reaction
Messenger RNA
Serum

ASJC Scopus subject areas

  • Transplantation

Cite this

In vivo depletion of CD8+ T cells results in Th2 cytokine production and alternate mechanisms of allograft rejection. / Chan, Sherri Y.; DeBruyne, Lisa A.; Goodman, Richard E.; Eichwald, Ernst J.; Bishop, D. Keith.

In: Transplantation, Vol. 59, No. 8, 27.04.1995, p. 1155-1161.

Research output: Contribution to journalArticle

Chan, Sherri Y. ; DeBruyne, Lisa A. ; Goodman, Richard E. ; Eichwald, Ernst J. ; Bishop, D. Keith. / In vivo depletion of CD8+ T cells results in Th2 cytokine production and alternate mechanisms of allograft rejection. In: Transplantation. 1995 ; Vol. 59, No. 8. pp. 1155-1161.
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AB - A current hypothesis states that Th1 cytokines promote allograft rejection and that Th2 cytokines promote graft acceptance. We present data that question the tolerogenic activity of Th2 cytokines, and we suggest that Th2 cytokines may evoke allograft rejection by recruitment of alternate effector mechanisms. Unmodified rejection of mouse heterotopic cardiac allografts is associated with the accumulation of large numbers of donor-reactive CD8+ CTL within the allograft, which is indicative of a Thl-driven cellular response. However, when recipients are depleted of CD8+ CTL, rejection still occurs and is associated with an aggressive cellular infiltrate rich in eosinophils, large mononuclear cells, and fibroblast-like cells. Eosinophils, which are responsive to the Th2 cytokines IL-4 and IL-5, are not present in unmodified rejecting allografts. Differential production of Thl versus Th2 cytokines was further suggested by altered levels of IgG2a (promoted by IFNγ) and IgGl (promoted by IL-4) alloantibody in the sera of these mice; IgG2a dominated the alloantibody response in unmodified allograft recipients, whereas IgG1 levels increased in recipients depleted of CD8+ CTL. Altered intragraft cytokine gene expression was verified by RT-PCR; Thl (IL-2, IFNγ), but not Th2 (IL-4, IL-5, IL-10), cytokine mRNAs were readily detectable in the allografts of unmodified recipients. In contrast, both Thl and Th2 cytokine genes were expressed in the allografts of mice depleted of CD8+ CTL. These data suggest that donor-reactive CD8+ CTL inhibit intragraft production of Th2 cytokines, thereby promoting a Thl domi-nated-rejection response. Elimination of CD8+ cells allows Th2 cytokine production, which may have deleterious, rather than protective, effects.

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