Viral-induced CD28 loss evokes costimulation independent alloimmunity

Abstract

Background Belatacept, a B7-specific fusion protein, blocks CD28-B7 costimulation and prevents kidney allograft rejection. However, it is ineffective in a sizable minority of patients. Although T cell receptor and CD28 engagement is known to initiate T cell activation, many human antigen-experienced T cells lose CD28, and can be activated independent of CD28 signals. We posit that these cells are central drivers of costimulation blockade resistant rejection (CoBRR) and propose that CoBRR might relate to an accumulation of CD28- T cells resulting from viral antigen exposure. Materials and Methods We infected C57BL/6 mice with Polyomavirus (a BK virus analog), murine cytomegalovirus (mCMV; a human CMV analog), and gammaherpes virus (HV68; an Epstein-Barr virus analog) and assessed for CD28 expression relative to mock infection controls. We then employed mixed lymphocyte reactions (MLR) assays to assess the alloreactive response of these mice against MHC-mismatched cells. Results We demonstrated that infection with Polyomavirus, murine CMV, and HV68 can induce CD28 down-regulation in mice. We showed that these analogs of clinically relevant human viruses enable lymphocytes from infected mice to launch an anamnestic, costimulation blockade resistant, alloreactive response against MHC-mismatched cells without prior alloantigen exposure. Further analysis revealed that gammherpesvirus-induced oligoclonal T cell expansion is required for the increased alloreactivity. Conclusion Virus exposure results in reduced T cell expression of CD28, the target of costimulation blockade therapy. These viruses also contribute to increased alloreactivity. Thus, CD28 down-regulation following viral infection may play a seminal role in driving CoBRR.

Memory T cells in organ transplantation: progress and challenges

“…Indeed, effector cells that express low levels of CD28 have been implicated in CD28–B7 co-stimulation-blockade-resistant allograft rejection 34,35 . Other subsets of CD28 − T cells that also express high levels of CD2, LFA-1 and VLA-4, are associated with rejection mediated by resistance to belatacept in human studies 36 .…”

“…Specific pathogens such as Listeria monocytogenes 44 , γ-herpes virus 45 and cytomegalovirus (CMV) 46,47 have been mechanistically defined in heterologous alloimmune processes. Indeed, in mice, these infections drive T-cell differentiation and the loss of CD28 expression, leading to indifference to CD28–B7 co-stimulation blockade 35 . This type of direct alloresponse might be an acute, rather than chronic, problem in transplant recipients, and understanding the spectrum of phenotypes and activation criteria of memory T cells could help to elucidate a means of specifically targeting alloreactive T cells without compromising host protective immunity.…”

Increased Pretransplant Frequency of CD28+ CD4+ TEM Predicts Belatacept-Resistant Rejection in Human Renal Transplant Recipients

“…Indeed, in vitro studies have shown that CD8 + CD28 null cell effector function is not impacted by the addition of belatacept to cell cultures . Based on these data, the prevailing hypothesis in the transplant immunology community is that CD4 + and/or CD8 + CD28 null cells mediate costimulation blockade‐resistant rejection , and that patients who reject their kidney graft during costimulation blockade may have increased pretransplant frequencies of CD4 + and/or CD8 + CD28 null T cells . Despite this assumption, there are no published reports correlating pretransplant CD4 + or CD8 + CD28 null frequency with risk of costimulation blockade‐resistant rejection.…”

T Cells Going Innate

“…Moreover, IL-15 has been shown to induce proliferation of alloreactive CD28 − memory CD8 + T cells that were subsequently resistant to CTLA-4-Ig blockade [90]. Recently, it has also been suggested that the loss of CD28 subsequent to viral infections facilitated the acquisition of co-stimulatory-independent alloimmune responses [91]. In support, viral infections prior to transplantation have been shown to abrogate skin graft survival following CTLA-4-Ig/anti-CD154 treatment [92].…”