Role of dendritic cell subsets in glomerulonephritis

我们最近报道，肾树突状细胞(KDC)的激活通过趋化因子介导的免疫效应细胞的募集，推动了人类新月体肾炎(CGN)模型--肾毒性肾炎(NTN)的进展。相反，未成熟的kDC通过趋化因子介导的免疫抑制自然杀伤T细胞(NKT细胞)和调节性T细胞(Treg)的募集来减弱CGN，它们的功能出人意料地依赖于转录因子NF-κB。此外，我们发现依赖BATF3的kDC在NTN中具有令人惊讶的强大保护功能。在下一个资助期，我们希望澄清依赖和不依赖于BATF3的kDC的作用机制。我们将1.研究BATF3依赖的kDC在系统性Th1细胞免疫应答中的作用；2.区分BATF3依赖和非依赖的kDC在NTN中的作用，特别关注与抑制性iNKT细胞和Tregs的潜在相互作用；3.通过区分保护性和促炎性DC之间的比例是否向后者转移，或者保护性DC是否成熟并失去保护功能，例如通过NF-κB；以及4.明确哪些KDC亚群迁移到NTN的肾淋巴结。我们期望了解DC在CGN中的作用及其调节功能可能有助于开发新的针对GN的DC靶向治疗。

We recently reported that activation of kidney dendritic cells (kDCs) drives progression of nephrotoxic glomerulonephritis (NTN), a model of human crescentic GN (cGN), by mechanisms involving chemokine-mediated recruitment of immune effector cells. By contrast, immature kDCs attenuated cGN by chemokine-mediated recruitment of immunosuppressive natural killer T cells (NKT cells) and regulatory T cells (Tregs,) whose function surprisingly depended on the transcription factor NF-κB. Furthermore, we found that Batf3-dependent kDCs, a small subset of DCs characterized in the kidney by CD103 expression, possess a surprisingly strong protective functionality in NTN. In the next funding period, we wish to clarify the mechanisms underlying the function of Batf3-dependent and -independent kDCs. We will 1. Study the role of Batf3-dependent kDCs on the systemic Th1 cell immune response against the kidney; 2. Distinguish between effects of Batf3-dependent and -independent kDCs in NTN, with a particular focus on potential interactions with suppressive iNKT cells and Tregs; 3. Clarify how kidney DC function turns pro-inflammatory in chronic NTN, by distinguishing whether the ratio between protective and pro-inflammatory DCs shifts towards the latter or whether protective DCs mature and lose their protective functionality, for example through NF-κB; and 4. Clarify which kDC subsets migrate to the renal lymph node in NTN. We expect that knowledge of the roles of DCs and their regulatory functions in cGN may facilitate developing new DC-targeted therapies for GN.