H2 Control of Natural T Regulatory Cell Frequency in the Lymph Node Correlates with Susceptibility to Day 3 Thymectomy-Induced Autoimmune Disease

Abstract

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) F1 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-ChrA/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-ChrXA/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-Chr17A/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.

Histamine H4 Receptor Optimizes T Regulatory Cell Frequency and Facilitates Anti-Inflammatory Responses within the Central Nervous System

“…We show here that H 4 R signaling has a significant impact on regulating the proportion and distribution of natural T R cells in secondary lymphoid organs but not on their thymic development. These results support the concept that specific factors in the microenvironment of peripheral lymphoid tissues may dictate the fate of the immune response by influencing T R cell biology (i.e., the frequency and distribution of T R ) (38, 39). Naïve H 4 RKO mice have lower frequency of peripheral T R cells than WT mice and, upon MOG 35-55 immunization, exhibit more severe EAE.…”

Genetics of experimental allergic encephalomyelitis supports the role of T helper cells in multiple sclerosis pathogenesis

“…The expression of Eae5 candidates in T H ‐cell pathways suggested that either CD4 T H cells or Tregs might be affected as a result of the inheritance of SJL alleles at Eae5 . The frequency of natural Tregs (nTregs) in the lymph node is under the control of a gene within or tightly linked to H2 (del Rio and colleagues 23). The Eae5 locus lies just distal to H2 (Fig 4).…”

“…IL‐2 signaling plays a key role in immunomodulation through control of regulatory T‐cell homeostasis and function. Indeed, small perturbations in IL‐2 levels or in Treg frequency have been associated with differential susceptibility to EAE 23, 32. In addition, the environmentally derived factor VitD is physiologically immunoregulatory due, in part, to positive effects on Tregs 33, 34.…”

Regulatory T cells control tolerogenic versus autoimmune response to sperm in vasectomy

“…According to our data, the resistance state of the B6 mice is a reflection of their strong intrinsic Treg function. This mechanism has been documented in autoimmune diabetes (35), and subsequently in autoimmune ovarian disease (36), autoimmune dacryoadenitis (37), and EAE (38). In all cases, disease resistance was mapped to the IL-2 locus in chromosome 3 (35), associated with enhanced production of IL-2 by activated T cells (35,39).…”