Original Article
Allo-HLA Cross-Reactivities of Cytomegalovirus-, Influenza-, and Varicella Zoster Virus–Specific Memory T Cells Are Shared by Different Healthy Individuals

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Virus-specific T cells can recognize allogeneic HLA (allo-HLA) through TCR cross-reactivity. The allospecificity often differs by individual (private cross-reactivity) but also can be shared by multiple individuals (public cross-reactivity); however, only a few examples of the latter have been described. Because these could facilitate alloreactivity prediction in transplantation, we aimed to identify novel public cross-reactivities of human virus-specific CD8+ T cells directed against allo-HLA by assessing their reactivity in mixed-lymphocyte reactions. Further characterization was done by studying TCR usage with primer-based DNA sequencing, cytokine production with ELISAs, and cytotoxicity with 51chromium-release assays. We identified three novel public allo-HLA cross-reactivities of human virus-specific CD8+ T cells. CMV B35/IPS CD8+ T cells cross-reacted with HLA-B51 and/or HLA-B58/B57 (23% of tetramer-positive individuals), FLU A2/GIL (influenza IMP[58-66] HLA-A*02:01/GILGFVFTL) CD8+ T cells with HLA-B38 (90% of tetramer-positive individuals), and VZV A2/ALW (varicella zoster virus IE62[593-601] HLA-A*02:01/ALWALPHAA) CD8+ T cells with HLA-B55 (two unrelated individuals). Cross-reactivity was tested against different cell types including endothelial and epithelial cells. All cross-reactive T cells expressed a memory phenotype, emphasizing the importance for transplantation. We conclude that public allo-HLA cross-reactivity of virus-specific memory T cells is not uncommon and may create novel opportunities for alloreactivity prediction and risk estimation in transplantation.

KEYWORDS

basic (laboratory) research/science
translational research/science
immunobiology
histocompatibility
organ transplantation in general
alloantigen
antigen presentation/recognition
immunogenetics
infection and infectious agents
viral
major histocompatibility complex (MHC)

Abbreviations

CFSE
carboxyfluorescein succinimidyl ester
CMV B35/IPS
cytomegalovirus pp65(123-131) HLA-B*35:01/IPSINVHHY
CMV
cytomegalovirus
CPM
counts per minute
EBV
Epstein–Barr virus
EBV-LCL
Epstein–Barr virus transformed lymphoblastoid cell line
FACS
fluorescence-activated cell sorting
FCS
fetal calf serum
FLU A2/GIL
influenza IMP(58-66) HLA-A*02:01/GILGFVFTL
FLU
influenza
HS
human serum
HUVEC
human umbilical vein endothelial cell
IFN-γ
interferon γ
IMDM
Iscove’s Modified Dulbecco’s Medium
MLR
mixed lymphocyte reaction
n.a.
not available
n.d.
no data
PBMC
peripheral blood mononuclear cell
PE
phycoerythrin
PHA
hytohemagglutinin
PTEC
proximal tubular epithelial cell
SI
stimulation index
VZV A2/ALW
varicella zoster virus IE62(593-601) HLA-A*02:01/ALWALPHAA
VZV
varicella zoster virus

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