Dendritic cell reprogramming by endogenously produced lactic acid

Aikaterini Nasi, Tünde Fekete, Akilan Krishnamurthy, Stuart Snowden, Eva Rajnavölgyi, Anca I. Catrina, Craig E. Wheelock, Nancy Vivar, Bence Rethi

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54 Citations (Scopus)

Abstract

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 g (PPARg), 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.

Original languageEnglish
Pages (from-to)3090-3099
Number of pages10
JournalJournal of Immunology
Volume191
Issue number6
DOIs
Publication statusPublished - Sep 15 2013

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Nasi, A., Fekete, T., Krishnamurthy, A., Snowden, S., Rajnavölgyi, E., Catrina, A. I., Wheelock, C. E., Vivar, N., & Rethi, B. (2013). Dendritic cell reprogramming by endogenously produced lactic acid. Journal of Immunology, 191(6), 3090-3099. https://doi.org/10.4049/jimmunol.1300772