Exogenous, TAP‐independent lysosomal presentation of a respiratory syncytial virus CTL epitope

Abstract

Respiratory syncytial virus causes lower respiratory tract infections in infancy and old age, affecting also immunocompromised patients. The viral fusion protein is an important vaccine candidate eliciting antibody and cell-mediated immune responses. CD8 þ cytotoxic T lymphocytes (CTLs) are known to have a role in both lung pathology and viral clearance. In BALB/c mice, the fusion protein epitope F249-258 is presented to CTLs by the murine major histocompatibility complex (MHC) class I molecule K d . In cells infected with recombinant vaccinia viruses encoding the fusion protein, F249-258 is presented by MHC class I molecules through pathways that are independent of the transporters associated with antigen processing (TAP). We have now found that F249-258 can be generated from non-infectious virus from an exogenous source. Antigen processing follows a lysosomal pathway that appears to require autophagy. As a practical consequence, inactivated virus suffices for in vivo priming of virus-specific CTLs. Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in infants and young children, 3 affecting also immunocompromised patients and the elderly. The fusion (F) glycoprotein of RSV is a major vaccine candidate as it is an important target for neutralising antibodies 4 and virus-specific CTLs. 5 Studies in the mouse model of human RSV have shown that CTLs have a role both in lung pathology and viral clearance. 6,7 In previous studies,

Intersection of autophagy with pathways of antigen presentation

“…Interestingly, unlike HSV-1 gB, Tey et al hypothesize that pUL138 degradation and subsequent generation and loading of the peptide into MHCI occurs in the autophagolysosome, where antigen does not access to the cytosol. A similar pathway of MHCI antigen presentation has also been described for an epitope derived from respiratory syncytial virus, where MHCI antigen presentation was abrogated in the presence of 3-MA treatment (Johnstone et al, 2012). Therefore autophagy-mediated MHCI presentation is a relevant pathway of antigen presentation for several virus-associated antigens and may, or may not, involve the classical MHCI antigen presentation route.…”

Checking the garbage bin for problems in the house, or how autophagy assists in antigen presentation to the immune system

“…While, however, HSV gB processing was still proteasome dependent, HCMV pUL138 degradation was proteasome independent, suggesting that maybe an endosomal MHC class I loading compartment requires macroautophagy for its formation, and can receive input from lysosomal or proteasomal antigen processing. Supporting this notion is the recent finding that crosspresentation of the F protein of the respiratory syncytial virus (RSV) also requires macroautophagy, but is independent of TAP and proceeds via lysosomal degradation [35].…”

The impact of macroautophagy on CD8+ T‐cell‐mediated antiviral immunity

“…Moreover, α‐Al 2 O 3 ‐OVA complex co‐localized with LC3 in DCs suggesting that autophagy can potentiate cross‐presentation of antigens by DCs through their targeting to autophagosomes. A study using respiratory syncytial virus (RSV) suggested that autophagy and lysosomal degradation are required for cross‐presentation of an RSV‐derived epitope by MHC I using a lymphoblastoid cell line deficient in TAP . Interestingly, results from Knittler and colleagues showed that autophagy targets intracellular Chlamydia during DC maturation after infection and that autophagic processing is necessary for Chlamydia epitope presentation onto MHC I .…”