MHC AFFINITY, PEPTIDE LIBERATION, T-CELL REPERTOIRE, AND IMMUNODOMINANCE ALL CONTRIBUTE TO THE PAUCITY OF MHC CLASS I-RESTRICTED PEPTIDES RECOGNIZED BY ANTIVIRAL CTL
Yp. Deng et al., MHC AFFINITY, PEPTIDE LIBERATION, T-CELL REPERTOIRE, AND IMMUNODOMINANCE ALL CONTRIBUTE TO THE PAUCITY OF MHC CLASS I-RESTRICTED PEPTIDES RECOGNIZED BY ANTIVIRAL CTL, The Journal of immunology, 158(4), 1997, pp. 1507-1515
MHC class I-restricted T cell responses to viral proteins focus on a l
imited set of peptides. To better understand this phenomenon, we exami
ned all of the 26 nonameric peptides encoded by the influenza virus A/
Puerto Rico/8/34 (PR8) conforming to the canonical K-d binding motif.
Ten peptides bound strongly to K-d as assessed by a cell surface stabi
lization assay, Five of these 10 induced in vitro secondary CD8(+) T c
ell responses from splenocytes derived from PR8-immunized mice. The st
rongest responses were induced by the two previously defined antigenic
peptides, which ranked only second and fifth in relative binding affi
nity. To examine the limiting factors in the immunogenicity of K-d-bin
ding peptides, we produced recombinant vaccinia viruses (rVVs) express
ing cytosolic or endoplasmic reticulum (ER)-targeted peptides, rVVs ex
pressing ER-targeted versions of the 7 peptides with the highest relat
ive affinities for K-d rescued K-d cell surface expression in T2 cells
, while those expressing the 3 lowest affinity peptides did not. The i
mmunogenicity of several, but not all, of the highest affinity peptide
s was greatly enhanced when expressed as VV-encoded cytosolic or ER-ta
rgeted peptides as compared with full length proteins. We conclude tha
t limitations in the immunogenicity of class I binding peptides reflec
ts, in order of decreasing importance, peptide liberation by cellular
proteases, T cell repertoire, and TAP-mediated peptide transport. We a
lso observed an additional important contributing factor: suppression
of T cell responses to nondominant peptides by an immunodominant pepti
de located in the same protein.