Asialo GM1+ CD8+ T cells play a critical role in costimulation blockade–resistant allograft rejection

Abstract

Simultaneous blockade of the CD40 and CD28 costimulatory pathways is an effective treatment strategy to promote allograft acceptance but does not lead to indefinite allograft survival. The immune mechanisms responsible for costimulation-independent rejection are not defined. Here we have studied the rejection responses of murine C57BL/6 recipients, which we show to be relatively resistant to inhibition by combined CD40/CD28 blockade. We demonstrate that asialo GM1 + CD8 + cells play a critical role in this costimulation blockade-resistant rejection. These results provide new insights into the costimulatory requirements for T-cell subsets and demonstrate for the first time that combined blockade of the CD40 and CD28 pathways does not adequately inhibit CD8-mediated skin allograft rejection. Furthermore, we provide evidence that asialo GM1 is a potentially important therapeutic target for CD8-dependent immune responses.

Primed Allospecific T Cells Prevent the Effects of Costimulatory Blockade on Prolonged Cardiac Allograft Survival in Mice

“…The resistance to the effects of costimulatory blockade was alloantigen specific in that B10.A DST/aCD40L was highly effective in the presence of T cells primed to an entirely separate set of alloantigens (Table 1). Our studies confirm previously published findings that naïve CD8 π T cells (28)(29)(30)(31), T cells primed to viral antigens (32,33), and in some cases CD4 π T cells (21,34) can be resistant to the effects of costimulatory blockade. DST/aCD40L fully prevented the expansion and activation of the alloreactive T cells in naïve animals transplanted with B10.A hearts (associated with prolonged graft survival, Figure 2).…”

Inability to Induce Tolerance Through Direct Antigen Presentation

“…Novel immunotherapeutic reagents, such as CTLA4Ig or anti-CD154, have been extremely effective in specifically blocking T-cell responses in vitro (24)(25)(26) and inducing long-term survival of organ and tissue allografts (33,35,(58)(59)(60). Notably, studies by Larsen and colleagues provided compelling evidence for the importance of CD28/ B7 and CD154/CD40 in CD4π T-cell-mediated skin allograft rejection (24,37). However, although initial studies in rodents supported an essential role for CD28/B7 and CD154/CD40 interactions in the allograft setting, an increasing number of exceptions have been described.…”

“…Subsequent studies confirmed that combined blockade specifically blocked CD4π T-cell-mediated allograft reactions (37). To determine whether CD4π T cells restricted to direct antigen presentation were susceptible to tolerance induction via costimulatory blockade, we used an adoptive transfer system in which B6.RAG-1-/-mice were reconstituted with B6 aBM12 TCR Tg T cells.…”

“…model when both the direct and indirect antigen presentation pathways were operational (24,37), combined treatment with anti-B7-1, anti-B7-2, and anti-CD154 mAbs did not prevent CD4π T-cell-mediated rejection in the B6 aBM12 TCR Tg direct-only system (R, MSTΩ 14.6 days, SE Ω 1.67, p Ω 0.058).…”

“…Numerous studies also indicated that the CD28/B7 and CD154/CD40 costimulatory pathways were critical regulators of allograft rejection (24,25,(27)(28)(29)(30)(31)(32)(33)(34)(35), Direct Class II Antigen Presentation and Tolerance specifically in CD4π T-cell-mediated rejection (36,37). Recent studies point to a differential role of CD28/B7 and CD154/CD40 costimulation in CD4 vs. CD8 T-cell-mediated allogeneic responses.…”