Dendritic Cell Reprogramming by Endogenously Produced Lactic Acid
Dendritic Cell Reprogramming by Endogenously Produced Lactic Acid
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DOI：
10.4049/jimmunol.1300772
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发表时间：
2013-09-15
影响因子：
4.4
通讯作者：
Rethi, Bence
中科院分区：
文献类型：
--
作者：
Nasi, Aikaterini;Fekete, Tuende;Rethi, Bence
通过树突状细胞（DC）疫苗控制T细胞应答的需求引发了对可靠且可行的DC调节策略的探索，所述DC调节策略将促进针对肿瘤的细胞毒性或自身免疫中的耐受性。我们研究了单核细胞来源的DC（MoDC）在分化过程中诱导炎症或抑制程序的内源性机制，我们确定了一个强大的自分泌途径，以细胞浓度依赖性的方式，强烈干扰炎性DC分化。在低细胞培养密度下发育的MoDC具有产生炎性细胞因子、诱导Th 1极化和向淋巴组织趋化因子CCL 19迁移的上级能力。相反，源自密集培养物的MoDC在活化时产生IL-10但不产生炎性细胞因子。高密度培养的DC具有更强的分化可塑性，可向破骨细胞分化。细胞浓度依赖性途径独立于过氧化物酶体增殖物激活受体γ（PPAR γ），一种已知的MoDC分化的内源性调节因子。相反，它通过乳酸起作用，乳酸在密集的培养物中积累，并诱导MoDC分化的早期和持久的重编程。我们的研究结果表明，乳酸介导的抑制途径可以有效地操纵在开发MoDC影响DC疫苗的免疫原性。
The demand for controlling T cell responses via dendritic cell (DC) vaccines initiated a quest for reliable and feasible DC modulatory strategies that would facilitate cytotoxicity against tumors or tolerance in autoimmunity. We studied endogenous mechanisms in developing monocyte-derived DCs (MoDCs) that can induce inflammatory or suppressor programs during differentiation, and we identified a powerful autocrine pathway that, in a cell concentration-dependent manner, strongly interferes with inflammatory DC differentiation. MoDCs developing at low cell culture density have superior ability to produce inflammatory cytokines, to induce Th1 polarization, and to migrate toward the lymphoid tissue chemokine CCL19. On the contrary, MoDCs originated from dense cultures produce IL-10 but no inflammatory cytokines upon activation. DCs from high-density cultures maintained more differentiation plasticity and can develop to osteoclasts. The cell concentration-dependent pathway was independent of peroxisome proliferator-activated receptor gamma (PPAR gamma), a known endogenous regulator of MoDC differentiation. Instead, it acted through lactic acid, which accumulated in dense cultures and induced an early and long-lasting reprogramming of MoDC differentiation. Our results suggest that the lactic acid-mediated inhibitory pathway could be efficiently manipulated in developing MoDCs to influence the immunogenicity of DC vaccines.