HLA-DQ6 and HLA-DQ8 transgenic mice respond to ragweed allergens and recognize a distinct set of epitopes on short and giant ragweed group 5 antigens.
We have investigated the genetic and molecular basis of immune responsiveness to short ragweed (SRW) (Ambrosia artemisiifolia) extract, and group 5 allergens from short and giant (Ambrosia trifida) ragweed using transgenic mice expressing DQ6 (HLA-DQA1*0103, HLA-DQB1*0601) and DQ8 (HLA-DQA1*0301, HLA-DQB1*0302) genes in class II knockout (A beta0) mice. Panels of overlapping peptides spanning the Amb a 5 and Amb t 5 Ags were synthesized. Mice were immunized with whole SRW extract or individual peptides s.c. and lymph node cells (LNC) were challenged in vitro. Strong T cell responses to SRW extract were measured in both HLA-DQ transgenic mice, while control, HLA-DQ6-/DQ8-/H-2A beta0, mice were unresponsive. IL-5 and IL-10 were the primary cytokines produced by in vitro challenged LNC of SRW-primed transgenic mice. HLA-DQ6-restricted T cell responses were detected to all three peptides of Amb t 5 and two determinants (residues 1-20 and 11-30) on Amb a 5. In contrast, LNC of HLA-DQ8 mice did not recognize peptide 11-30 of Amb t 5 Ag, but recognized several Amb a 5 determinants. The immune response in transgenic mice was dependent upon CD4+ T cells and was HLA-DQ restricted. Primed with purified Amb t 5, both transgenics recognized peptide 21-40, and an additional DQ6-restricted epitope was found within residue 1-20. SRW-immunized HLA-DQ6 mice respond to peptide 11-30 of Amb a 5, while HLA-DQ8 mice strongly recognize peptide 1-20. These results demonstrate the specificity of HLA class II polymorphism in allergen sensitivity and pave the way for developing antagonistic peptides for desensitization.
Chapoval
S P
SP
Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA.
Neeno
T
T
Krco
C J
CJ
Marietta
E V
EV
Harders
J
J
David
C S
CS
D000485:Allergens / Q000008:administration & dosage / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D052179:Antigens, Plant; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000235:genetics* / Q000276:immunology; D016056:Immunodominant Epitopes / Q000276:immunology; D007279:Injections, Subcutaneous; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology; D010455:Peptides / Q000008:administration & dosage / Q000276:immunology*; D010940:Plant Proteins / Q000008:administration & dosage / Q000276:immunology*; D011058:Pollen / Q000276:immunology*; D011108:Polymers; D018418:Th2 Cells / Q000378:metabolism
D000485:Allergens; D052179:Antigens, Plant; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D006683:HLA-DQ Antigens; C063831:HLA-DQ6 antigen; C109756:HLA-DQ8 antigen; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D010455:Peptides; D010940:Plant Proteins; D011108:Polymers; C029134:short ragweed fraction A-D-glutamic acid-D-lysine polymer; C069543:group 5 allergens, Ambrosia