Quantitative and Functional Diversity of Cross-Reactive EBV-Specific CD8+ T Cells in a Longitudinal Study Cohort of Lung Transplant Recipients

Abstract

We report, for the first time, the longitudinal measurement of cross-reactive FLR-specific CD8 T cells within a clinical transplantation framework.

Recognition of Distinct Cross-Reactive Virus-Specific CD8+ T Cells Reveals a Unique TCR Signature in a Clinical Setting

“…Our previous work has shown the ability of cross-reactive EBVspecific T cells to induce immune reactivity toward HLA molecules expressed on both PBMCs and BAL mononuclear cells (20,23,26). Of particular importance, a seminal study confirmed that recognition of allogeneic HLA molecules by virus-specific memory T cells is dependent on self-peptide presentation by the allogeneic target cell (57).…”

“…Three less frequent TCRs with different TRVab and TRJab usage were also observed, one having public a and b motifs ( n TSYDKV and SSAYYGY, respectively; n = variable number of amino acids) and one having a public a motif ( n GNQF; Table II, underlined). However, after stimulation with C1R.B27 allelic target cells, there was a shift in immunodominance toward clonotypes that had (20,7, and 0%, respectively). In these experiments, CD8 + tetramer + cells were sorted on very low to background levels of IFN-g because of poorer functional responses observed with these subtypes.…”

“…Previously, we have reported that cross-reactive antiviral T cells constitute a significant proportion of the alloreactive T cell pool, but there was no association with allograft rejection in the absence of active viral infection; thus, there was no potential amplification of the cross-reactive T cell pool (20). Building on this knowledge, we hypothesized that an active viral infection may be a major amplifier of the destructive potential of cross-reactive T cells (19).…”

“…Earlier reports examining the contribution of cross-reactive antiviral T cells toward allograft rejection in lung transplant recipients (LTRs) from our group (20) and graft-versushost disease in hematopoietic stem cell transplant recipients (21) demonstrated that cross-reactive antiviral T cells represented a significant proportion of the alloreactive T cell pool. However, in our previous EBV study, we revealed that baseline frequencies of the cross-reactive T cell pool remained unaltered in the absence of EBV reactivation (thereby potentially negating their ability to become activated, expand, and exert clinically significant damage toward the allograft) (20).…”

Update on lung transplantation: programmes, patients and prospects

“…This will be discussed in more detail for EBV (the second most problematic herpes virus for LTR) in relation to post-transplant lymphoproliferative disease (PTLD) [197][198][199][200]. Importantly, sub-clinical EBV reactivation may also specifically influence lung allograft outcomes through non-lytic virus effects [201,202], stimulating an activated immuno-inflammatory phenotype [203] and the potential for generating crossreactive antiviral memory T-cells [204]. Finally, these concepts are perhaps also important for non-herpes viridae DNA viruses such as human papilloma viruses, hepatitis B and C viruses and parvoviruses, all of which may cause significant problems in individual LTR [205,206].…”