CD8+ T cell subsets TC1 and TC2 cause different histopathologic forms of murine cardiac allograft rejection.

BACKGROUND: CD4+ T cell effector function is sufficient to mediate allograft rejection, and it is suggested that CD8+ T cell-mediated effects are dependent on CD4+ T cell help. CD8+ T cells can be classified into at least two functional subsets: Tc1, producing high amounts of interferon (IFN)-gamma and Tc2, producing interleukin (IL)-4, -5, -10, and -13 and low levels of IFN-gamma. Because these subsets express different chemokine receptors, they may have different capabilities of migrating into grafts. Once in the graft, each subset may perform different effector functions dependent on the cytokines it produces. We asked whether allospecific CD8+ T cells, in the absence of CD4+ T cells, are capable of mediating rejection of a primarily vascularized allograft, and if Tcl and Tc2 cells differ in their ability to mediate rejection. METHODS: Hearts from H-2d mice were transplanted into H-2b RAG 1-/- recipients. Without manipulation, these fully mismatched allografts would survive indefinitely due to the absence of mature T and B cells. We adoptively transferred allo-(H-2d)-reactive Tcl or Tc2 cells from H-2b mice into each recipient. Grafts were harvested and analyzed on predefined timepoints, rejection was graded on a modified ISHLT scale. RESULTS: On day 7, grafts from Tc1- or Tc2-injected animals showed grade 1-2 parenchymal rejection with stable phenotype and comparable distribution of graft infiltrating CD8+ T cells. Adoptive transfer of IFN-gammahigh Tc1, but not of IFN-gammalow Tc2 cells was followed by the development of graft vasculitis, as well as graft arteriopathy. Adoptive transfer of IL-4high IL-5high Tc2, but not of IL-4low IL-5low Tc1 cells lead to extensive infiltration of eosinophils and formation of giant cells. CONCLUSIONS: Both Tc1 and Tc2 cells can mediate murine cardiac allograft rejection in the absence of CD4+ T cell help, although each subset elicits a different type of inflammatory response. In this model, cytokine secretion of either functional CD8+ T effector cell subset is an important effector mechanism in the process of allograft rejection: IFN-gammahigh Tc1 cells are important in early graft vasculitis, although IL-4high IL-5high Tc2 cells promote recruitment of secondary effectors like eosinophils.

Tob is a negative regulator of activation that is expressed in anergic and quiescent T cells.

During a search for genes that maintain T cell quiescence, we determined that Tob, a member of an anti-proliferative gene family, was highly expressed in anergic T cell clones. Tob was also expressed in unstimulated peripheral blood T lymphocytes and down-regulated during activation. Forced expression of Tob inhibited T cell proliferation and transcription of cytokines and cyclins. In contrast, suppression of Tob with an antisense oligonucleotide augmented CD3-mediated responses and abrogated the requirement of costimulation for maximal proliferation and cytokine secretion. Tob associated with Smad2 and Smad4 and enhanced Smad DNA-binding. The inhibitory effect of Tob on interleukin 2 (IL-2) transcription was not mediated by blockade of NFAT, AP-1 or NF-kappaB transactivation but by enhancement of Smad binding on the -105 negative regulatory element of the IL-2 promoter. Thus, T cell quiescence is an actively maintained phenotype that must be suppressed for T cell activation to occur.