Impaired CD8+ T cell immunity after allogeneic bone marrow transplantation leads to persistent and severe respiratory viral infection

Abstract

Rationale Bone marrow transplant (BMT) recipients experience frequent and severe respiratory viral infections (RVI). However, the immunological mechanisms predisposing to RVIs are uncertain. Therefore, we hypothesized that antiviral T cell immunity is impaired as a consequence of allogeneic BMT, independent of pharmacologic immunosuppression, and is responsible for increased susceptibility to RVI. Methods Bone marrow and splenocytes from C57BL/6(H2b) mice were transplanted into B10.BR(H2k) (Allo) or C57BL/6(H2b) (Syn) recipients. Five weeks after transplantation, these mice were inoculated intranasally with mouse parainfluenza virus type 1 (mPIV-1), commonly known as Sendai virus (SeV), and monitored for relevant immunological and disease endpoints. Main Results Severe and persistent airway inflammation, epithelial injury, and enhanced mortality are found after viral infection in Allo mice but not in control Syn and non-transplanted mice. In addition, viral clearance is delayed in Allo mice as evidenced by prolonged detection of viral transcripts at Day 15 post-inoculation (p.i.) but not in control mice. In concert with these events, we also detected decreased levels of total and virus-specific CD8+ T cells, as well as increased T cell-expression of inhibitory receptor programmed death-1 (PD-1), in the lungs of Allo mice at Day 8 p.i. Adoptive transfer of CD8+ T cells from non-transplanted mice recovered from SeV infection into Allo mice at Day 8 p.i. restored normal levels of viral clearance, epithelial repair and lung inflammation. Conclusions Taken together these results indicate that allogeneic BMT results in more severe RVI based on the failure to develop an appropriate pulmonary CD8+ T cell response, providing an important potential mechanism to target in improving outcomes of RVI after BMT.

Prostaglandin E2 Production and T Cell Function in Mouse Adenovirus Type 1 Infection following Allogeneic Bone Marrow Transplantation

“…While PGE 2 overproduction was apparently not the cause of T cell dysfunction, our data indicate that aberrant T cell function in allogeneic BMT mice is a potential explanation for delayed virus clearance. This is similar to findings in a recent study indicating that impaired clearance of Sendai virus in allogeneic BMT is due to T cell dysfunction [ 51 ]. In our study, CD8α -/- mice had higher viral loads than CD8α +/+ mice at 14 dpi, suggesting that CD8α -/- mice had a defect in clearance of virus from the lungs similar to that observed in allogeneic BMT mice.…”

“…Because delayed virus clearance in BMT mice was not a consequence of PGE 2 overproduction, we considered other aspects of immune function that could affect MAV-1 clearance during BMT. Impaired CD8 T cell immunity contributes to increased severity of disease caused by Sendai virus in allogeneic BMT mice [ 51 ]. We therefore hypothesized that the inability of allogeneic BMT mice to efficiently clear virus from the lungs could be due to impaired T cell recruitment or function during MAV-1 infection.…”

“…GzmB, perforin or Fas/FasL signaling), since MAV-1 clearance was similarly impaired in CD8α -/- mice but not IFN-γ -/- mice. It is possible that CD8 T cell dysfunction in allogeneic BMT mice infected with MAV-1 was due to enhanced suppression via interactions between programmed death 1 and PD-1 ligand proteins, as is the case with Sendai virus infection in allogeneic BMT [ 51 ]. Future studies will systematically address which CD8 effector functions are most critical for clearance of MAV-1 as well as the specific mechanisms underlying T cell dysfunction post-BMT.…”

Effects of Hematopoietic Cell Transplantation on the Pulmonary Immune Response to Infection

“…This was associated with decreased recruitment of both total and virus specific CD8 + T cells to the lungs in allogeneic HCT mice, and was improved by adoptive transfer of CD8 + cells from un-transplanted mice recovering from Sendai virus infection. Interestingly, syngeneic HCT mice had similar results to un-transplanted mice after infection (64). In a mouse model of adenovirus infection after allogeneic HCT, McCarthy et al showed that HCT mice had delayed viral clearance, and although pulmonary PGE 2 production was increased, the reduced production of IFN-γ and granzyme B and the delayed viral clearing noted in pulmonary CD8 + T-cells appeared independent of elevated PGE 2 production (65).…”

“…The pulmonary immune responses to these viruses after HCT are less well-described. Gowdy et al examined the effect of the respiratory viral pathogen mouse parainfluenza virus type 1 (mPIV-1), also known as Sendai virus, in both syngeneic and allogeneic HCT mice ( 64 ). Allogeneic HCT mice had increased viral load, decreased survival, and increased pulmonary inflammation after Sendai virus infection.…”