HLA-A*26, HLA-B*4002, HLA-B*4006, and HLA-B*4801 alleles predispose to adult T cell leukemia: the limited recognition of HTLV type 1 tax peptide anchor motifs and epitopes to generate anti-HTLV type 1 tax CD8(+) cytotoxic T lymphocytes.
Genetic risk for adult T cell leukemia (ATL) has been implicated by ethnic and familial segregation of ATL patients from HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). To clarify the genetic risk for ATL, we characterized HLA class I alleles of ATL patients and analyzed the anchor motifs of HTLV-1 peptides binding to HLA class I molecules, using 291 lines of anti-HTLV-1 CD8(+) cytotoxic T lymphocytes (CTLs) generated in vitro with a total of 165 synthetic peptides for HTLV-1 Tax and Env proteins. Allele frequencies of HLA-A*26, B*4002, B*4006, and B*4801 were significantly higher in ATL patients than in HAM/TSP patients and asymptomatic HTLV-1 carriers in southern Japan. CD8(+) CTL analysis revealed the HTLV-1 Tax peptide sequence to completely lack anchor motifs of peptides binding to HLA-A*26,B*4002, and B*4006 molecules but to possess one anchor for HLA-B*4801, while the HTLV-1 Env peptide sequence had many anchor motifs for HLA-A*26, B*4002, B*4006, and B*4801 molecules. Most ATL patients featured heterozygous HLA class I alleles composed of HLA-A*26, B*4002, B*4006, and B*4801, with a lower number of HTLV-1 Tax peptide anchor motifs and epitopes generating anti-HTLV-1 Tax CD8(+) CTLs than individuals possessing other HLA alleles. The relationship between Tax epitope and ATL incidence was verified by the significantly decreased number of HTLV-1 Tax epitopes in ATL patients compared with asymptomatic HTLV-1 carriers (p < 0.01) as well as late onset ATL patients (p < 0.001). These results indicate that HLA-A*26, B*4002, B*4006, and B*4801 alleles predispose to ATL because of the limited recognition of HTLV-1 Tax peptide anchor motifs and epitopes capable of generating anti-HTLV-1 Tax CD8(+) CTLs.
Yashiki
S
S
Department of Virology, Faculty of Medicine, Kagoshima University, Kagoshima 890-8520, Japan.
Fujiyoshi
T
T
Arima
N
N
Osame
M
M
Yoshinaga
M
M
Nagata
Y
Y
Tara
M
M
Nomura
K
K
Utsunomiya
A
A
Hanada
S
S
Tajima
K
K
Sonoda
S
S
D000328:Adult; D000367:Age Factors; D000368:Aged; D000483:Alleles; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002353:Carrier State / Q000276:immunology / Q000821:virology; D002460:Cell Line; D000939:Epitopes; D005260:Female; D016356:Gene Products, tax / Q000276:immunology*; D005805:Genes, MHC Class I / Q000235:genetics; D020022:Genetic Predisposition to Disease; D015234:HLA-A Antigens / Q000235:genetics*; D015235:HLA-B Antigens / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D007564:Japan; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000276:immunology
D000939:Epitopes; D016356:Gene Products, tax; D015234:HLA-A Antigens; C039683:HLA-A*26 antigen; D015235:HLA-B Antigens; D014759:Viral Envelope Proteins