H2 control of natural T regulatory cell frequency in the lymph node correlates with susceptibility to day 3 thymectomy-induced autoimmune disease.
Day 3 thymectomy (D3Tx) results in a loss of peripheral tolerance mediated by natural regulatory T cells (nTregs) and development of autoimmune ovarian dysgenesis (AOD) and autoimmune dacryoadenitis (ADA) in A/J and (C57BL/6J × A/J) F(1) hybrids (B6A), but not in C57BL/6J (B6) mice. Previously, using quantitative trait locus (QTL) linkage analysis, we showed that D3Tx-AOD is controlled by five unlinked QTL (Aod1-Aod5) and H2. In this study, using D3Tx B6-Chr(A/J)/NaJ chromosome (Chr) substitution strains, we confirm that QTL on Chr16 (Aod1a/Aod1b), Chr3 (Aod2), Chr1 (Aod3), Chr2 (Aod4), Chr7 (Aod5), and Chr17 (H2) control D3Tx-AOD susceptibility. In addition, we also present data mapping QTL controlling D3Tx-ADA to Chr17 (Ada1/H2), Chr1 (Ada2), and Chr3 (Ada3). Importantly, B6-ChrX(A/J) mice were as resistant to D3Tx-AOD and D3Tx-ADA as B6 mice, thereby excluding Foxp3 as a susceptibility gene in these models. Moreover, we report quantitative differences in the frequency of nTregs in the lymph nodes (LNs), but not spleen or thymus, of AOD/ADA-resistant B6 and AOD/ADA-susceptible A/J, B6A, and B6-Chr17(A/J) mice. Similar results correlating with experimental allergic encephalomyelitis and orchitis susceptibility were seen with B10.S and SJL/J mice. Using H2-congenic mice, we show that the observed difference in frequency of LN nTregs is controlled by Ada1/H2. These data support the existence of an LN-specific, H2-controlled mechanism regulating the prevalence of nTregs in autoimmune disease susceptibility.
Department of Medicine, University of Vermont, Burlington, VT 05405, USA.
Roxana
R
del Rio
Yuefang
Y
Sun
Pascale
P
Alard
Kenneth S K
KS
Tung
Cory
C
Teuscher
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000601:surgery; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D002875:Chromosomes / Q000235:genetics; D003607:Dacryocystitis / Q000235:genetics / Q000276:immunology; D004198:Disease Susceptibility / Q000276:immunology; D005260:Female; D008040:Genetic Linkage / Q000276:immunology; D006183:H-2 Antigens / Q000502:physiology*; D008198:Lymph Nodes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D018655:Lymphocyte Count; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009869:Oophoritis / Q000235:genetics / Q000276:immunology*; D040641:Quantitative Trait Loci / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology*; D013934:Thymectomy
D006183:H-2 Antigens