Heterologous Immunity Triggered by a Single, Latent Virus in Mus musculus: Combined Costimulation- and Adhesion- Blockade Decrease Rejection

Abstract

The mechanisms underlying latent-virus-mediated heterologous immunity, and subsequent transplant rejection, especially in the setting of T cell costimulation blockade, remain undetermined. To address this, we have utilized MHV68 to develop a rodent model of latent virus-induced heterologous alloimmunity. MHV68 infection was correlated with multimodal immune deviation, which included increased secretion of CXCL9 and CXCL10, and with the expansion of a CD8dim T cell population. CD8dim T cells exhibited decreased expression of multiple costimulation molecules and increased expression of two adhesion molecules, LFA-1 and VLA-4. In the setting of MHV68 latency, recipients demonstrated accelerated costimulation blockade-resistant rejection of skin allografts compared to non-infected animals (MST 13.5 d in infected animals vs 22 d in non-infected animals, p<.0001). In contrast, the duration of graft acceptance was equivalent between non-infected and infected animals when treated with combined anti-LFA-1/anti-VLA-4 adhesion blockade (MST 24 d for non-infected and 27 d for infected, p = n.s.). The combination of CTLA-4-Ig/anti-CD154-based costimulation blockade+anti-LFA-1/anti-VLA-4-based adhesion blockade led to prolonged graft acceptance in both non-infected and infected cohorts (MST>100 d for both, p<.0001 versus costimulation blockade for either). While in the non-infected cohort, either CTLA-4-Ig or anti-CD154 alone could effectively pair with adhesion blockade to prolong allograft acceptance, in infected animals, the prolonged acceptance of skin grafts could only be recapitulated when anti-LFA-1 and anti-VLA-4 antibodies were combined with anti-CD154 (without CTLA-4-Ig, MST>100 d). Graft acceptance was significantly impaired when CTLA-4-Ig alone (no anti-CD154) was combined with adhesion blockade (MST 41 d). These results suggest that in the setting of MHV68 infection, synergy occurs predominantly between adhesion pathways and CD154-based costimulation, and that combined targeting of both pathways may be required to overcome the increased risk of rejection that occurs in the setting of latent-virus-mediated immune deviation.

Memory T cells in organ transplantation: progress and challenges

“…Adams et al elegantly showed that memory T cells from mice that had multiple infections could cross-react with alloantigens and mediate the rejection of skin allografts in the setting of co-stimulation blockade 43 . 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 .…”

“…Targeting VLA-4 in conjunction with co-stimulation blockade also increased survival in rodent transplant models compared to co-stimulation blockade alone 113 . Thus, inhibition of LFA-1 or VLA-4 in combination with co-stimulation blockade might have a synergistic effect, particularly in the setting of heterologous memory, whereby inhibition of integrin binding might selectively target cells that are resistant to co-stimulation blockade 47,100 .…”

Chronic Alcohol Ingestion Delays T Cell Activation and Effector Function in Sepsis

“…It has been previously reported that as CD8+ T cells become activated, they downregulate their CD8 surface expression, resulting in a population of so-called CD8 dim cells [26]. In our analyses, we noted that during sepsis a population of CD8 dim CD44 hi cells could be identified.…”

“…Furthermore, we identified a population of CD8 dim CD44 hi cells that emerged during sepsis which was significantly decreased in alcohol fed animals compared with water-fed animals 72 hours after CLP. Several published reports [26, 46] suggest that these may be antigen-specific CD8+ T cells that have downregulated the CD8 co-receptor following TCR ligation, and if so these findings would indicate a delay in expansion of antigen-specific CD8+ T cells following sepsis in the setting of chronic alcohol exposure. Future experiments using tools to track antigen-specific cell responses are likely warranted to further elucidate this relationship.…”

The Microbiome, Systemic Immune Function, and Allotransplantation

“…This effect was attributed to cross-reactive CD4 memory responses to Leishmania (15). Latent infections of B6 mice with murine gamma herpesvirus 68, a murine Epstein-Barr virus (EBV) homolog, accelerate BALB/c skin allograft rejection mediated by long-lasting viral antigen-specific CD8 memory responses (16,17). In transplant recipients receiving calcineurin inhibitorbased immunosuppression, persistent alloimmune responses generated by chronic viral infections do not become "exhausted" and may contribute to graft injury (18)(19)(20)(21).…”