Gastroenterology
Volume 137, Issue 5 , Pages 1566-1570, November 2009

Interleukin-23: Linking Mesenteric Lymph Node Dendritic Cells With Th1 Immunity in Crohn's Disease

  • Maria Rescigno

      Affiliations

    • Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
    • Corresponding Author InformationReprint requests Address requests for reprints to: Maria Rescigno, PhD, Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti, 435, 20141 Milan, Italy
    • ,
  • Iliyan D. Iliev

      Affiliations

    • Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California

published online 28 September 2009.

Article Outline

 

See “Th1/Th17 immune response is induced by mesenteric lymph node dendritic cells in Crohn's disease,” by Sakuraba A, Sato T, Kamada N, et al, on page 1736.

The immunopathology of inflammatory bowel diseases (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), remains unclear. Dysfunctions in the mucosal immune system and exaggerated immune responses to components of the microbiota have been proposed as contributing to the pathogenesis of IBD in genetically predisposed individuals.1 However, the mechanisms and players for these responses remain to be identified.

Dendritic cells (DC) are specialized antigen presenting cells that can initiate both immunity—humoral and cellular—and tolerance. These 2 capacities are dependent on the activation state of the DC, the analyzed subsets and their tissue of origin.2, 3 In the gut mucosa, for instance, different subsets of DC are endowed with specialized mucosal functions. These include the capacity to drive the differentiation of T-regulatory or Th17 cells, to drive the development of immunoglobulin (Ig)-A producing B cells and to imprint gut-homing properties to lymphocytes (reviewed in Rescigno and Di Sabatino2 Coombes and Powrie,4 and Kelsall5).

Why are mucosal DC so specialized? The symbiosis of the gut with the commensal flora allows to fully degrade even complex macromolecules present in the ingested food. Thus, the mucosal immune system has evolved the capacity to tolerate the microbiota, but also to immunosurveille for the presence of invaders, and DC are key players in these functions.

Under steady-state conditions, mouse lamina propria (LP) DC can be distinguished based on the expression of the integrin CD103,6 which recognizes E-cadherin. CD103+ DC are tolerogenic as they can drive the differentiation of T-regulatory cells (Tregs), the effectors of tolerance.6 CD103− DC drive the development of Th17 cells7, 8, 9 and IgA class-switched B cells.8 In the mesenteric lymph nodes (MLN), DC can also be distinguished based on the expression of CD103. Similarly to LP DC, mouse and human MLN CD103+ DC are involved in the induction of Tregs via a transforming growth factor (TGF)-β and retinoic acid (RA)-dependent mechanism.6, 10, 11, 12 In contrast, CD103− DC are more immunostimulatory and induce strong Th1 responses.6, 10, 11, 12

Given the important role of mucosal DC in dictating the outcome of an immune response, recent reports have analyzed their contribution to colitis development. MLN CD103+ DC have been shown to be involved in T-cell–mediated regulation of experimental colitis,13 whereas simultaneous depletion of both DC and macrophages before the induction of dextran sodium sulphate colitis, results in colitis exacerbation in mice.14 Similarly, tolerogenic DC are protective against colitis15 or can generate colitis-protective Tregs.11 In contrast, conditional depletion of conventional DC after the induction of dextran sodium sulphate colitis has an opposite effect and results in significant suppression of disease activity.16 These results suggest that, in the mouse, DC play an important role in the suppression of intestinal inflammation and maintenance of gut homeostasis before the onset of colitis, although they could exacerbate the disease at later times, supposedly because of their activation by bacterial antigens and inflammatory mediators.

Important evidence for the role of DC in human intestinal inflammation comes from studies in CD patients. Monocytes derived DC from CD patients carrying mutations in the NOD2 gene that has been associated with susceptibility to CD, display differential behavior, according to the carried mutation, in response to bacteria17 or to muramyl dipeptide,18 the ligand of NOD2. In addition, DC isolated directly from the LP of inflamed tissues of CD patients show an activated phenotype, suggesting that they are retained in situ.19

Among the different mediators of colitis, interleukin (IL)-23 has recently received much attention because genome wide association studies have pointed to IL-23 receptor (IL-23R) as an IBD-associated gene.20 In addition, LP CD4+ T cells isolated from IBD patients display an increased IL-23R and RA-related orphan receptor expression, which correlates with increased expression of IL-17.21 The role of IL-23 in colitis is further supported by functional studies in the mouse. IL-23 expression by non–T cells worsens the development of T-cell–dependent colitis, independent of IL-17 expression by T cells,22 whereas an antibody to the p19 subunit of IL-23 prevents and treats bacteria-specific driven T-cell colitis.23

Together, these studies suggest that DC can participate to colitis development and point to IL-23 as an important mediator of inflammation in IBD patients; however, important questions remain. These include how do DC participate to IBD development, can they release IL-23 in the MLN and activate pathogenic Th1 or Th17 cells and what is the function of IL-23?

The study by Sakuraba et al24 in this issue of Gastroenterology attempts to answer some of these questions by analyzing the phenotype and function of DC in MLN from IBD patients. Comparative analysis of CD4+ T cells isolated from MLN revealed a significant increase in Th1 and Th17 cells in MLN of CD patients compared with normal controls and UC. This correlated with an increased expression of the transcription factors Tbet and RA-related orphan receptor that are master regulators of Th1 and Th17 commitment, respectively. The authors then analyzed the phenotype and function of MLN DC to understand whether their activity could explain this preferential bias toward Th1 and Th17 cells. MLN DC from both CD and UC patients displayed a strong stimulatory activity on T cells, but only in CD patients was there an increased ratio of conventional (myeloid, mDC) versus plasmacytoid (pDC) DC. Furthermore, mDC, but not pDC, isolated from MLN of CD patients initiated potent Th1 responses. However, although MLN DC form CD patients displayed an increased ability to drive Th17 development; still, the percentage of generated Th17 cells was minimal.

Because MLN DC are poor Th17 inducers, the observed increase of Th17 cells in the LP and MLN of CD patients raises the question of which APC promote their differentiation. Th17 cells might be primed directly in the LP and later migrate to the MLN. As mentioned, in support to this hypothesis, CD103− LP DC have been shown to induce Th17 polarization.7, 8, 9 In addition, cytophaga-flavobacter-bacteroidetes are crucial for the induction of Th17 in the LP.25 Thus, LP DC exposed to commensal bacteria and their metabolites may be inducing Th17 differentiation directly in the LP. Alternatively, a small amount of Th17 cells might be induced in MLN or Peyer's patches and then restimulated in the LP by local APC. In this regard, a population of LP CD70+ APC has been identified as a potent inducer of T-cell proliferation26 and inhibition of the interaction of CD70 with its ligand CD27 has been shown to suppress experimental colitis in mice.27 In addition, macrophages may be involved in Th17 cell restimulation in the LP of CD patients or may migrate to the MLN to initiate Th17 cell responses28; however, the migration of macrophages to MLN for T-cell priming has not been described.

Sakaruba et al24 have also shown that upon stimulation with LPS or bacterial extracts, MLN DC from CD patients, released significantly higher amounts of IL-23, but lower amounts of IL-10 as compared with MLN DC from UC patients or normal controls. This is an important observation; MLN of CD patients display frequent granuloma formation, a condition previously associated with increased IL-23 production by mDC and persistent Th1 response in mice.29 Hence, the present study provides important evidence that MLN DC of CD patients differ from those isolated from healthy individuals or UC patients being highly producers of IL-23 that is involved in driving Th1 T-cell development. MLN DC may thus be involved in CD pathogenesis via the initiation of potent inflammatory Th1 T cells (Figure 1).

  • View full-size image.
  • Figure 1. 

    Human MLN are populated by conventional (cDC) and pDC. In healthy individuals, CD103+ cDC express CCR7, migrate from the LP to the MLN, where they release RA and TGF-β, and are able to prime tolerogenic T-cell responses. In contrast, CD103− DC produce IL-12 upon stimulation and are responsible for Th1 cell induction. cDC from MLN of UC patients, which produce IL-12 and IL-10 but not IL-23, are also able to induce Th1 responses, but at a lesser extent. UC has been further characterized with prevalent Th17 and Th2 infiltration in the LP. In MLN of CD patients, cDC outnumber pDC. In addition, activated cDC release IL-12 and IL-23 and are highly prone to prime inflammatory Th1 responses, with presumably concomitant reduction of Treg cell development. This correlates with significant Th1 and Th17 infiltration in the LP of CD patients. What drives the development of Th17 cells remains to be understood. Red bar, Th1/Th17 prevalence in the LP; NC, normal controls; UC, ulcerative colitis; CD, Crohn's disease.

One interesting question that rises from this report is where do these inflammatory DC come from? Under steady state, CCR7 a marker associated with DC migration from the LP,30 is expressed by CD103+ MLN DC that induce Treg development and limit Th1 responses.12 Hence, it would be interesting to know whether these inflammatory DC still express CD103 but have lost their tolerogenic potential. Indeed, the tolerogenic phenotype of human mucosal DC is conferred by the LP local microenvironment and in particular by epithelial cells via the release of specific tolerogenic mediators, such as TGF-β, RA, and thymic stromal lymphopoietin.12 In addition, epithelial cells from CD patients are impaired in the expression of these mediators and this correlates with the inability to control DC function leading to Th1 polarization.12 Hence, it is possible that the Th1-iducing MLN DC derive from the LP where they failed to become tolerogenic owing to the defective local microenvironment. Alternatively, these gut inflammatory DC may differentiate from blood precursors,31 after their transit in the inflamed regions of LP. They may represent the MLN counterpart of a new subset of CD205+CD209+ LP DC that are enriched in the LP of CD patients and share markers with macrophages like CD14 and CD68.32 Similar to MLN DC described by Sakuraba et al,24 CD205+CD209+ DC have been shown to produce large amounts of IL-23 in response to bacteria and to drive strong Th1 T-cell polarization.32

In conclusion, DC seem to play an important role in the differentiation of Th1 T cells during CD. Whether this is a consequence of the ongoing inflammation or is a primary defect of the DC remains to be established. It is worth noting that DC are an important source of IL-23 in CD. As mentioned, IL-23 has been recognized as a crucial mediator of this pathology, and at least in the mouse is more important than IL-17. Hence, the identification of the cells that highly produce IL-23 in MLN and are responsible for Th1 priming identifies DC as a possible therapeutic target for CD.

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 Conflicts of interest The author discloses no conflicts.

PII: S0016-5085(09)01670-9

doi:10.1053/j.gastro.2009.09.029

Refers to article:

  • Editorial Accompanies Article Th1/Th17 Immune Response Is Induced by Mesenteric Lymph Node Dendritic Cells in Crohn's Disease , 27 July 2009

    Atsushi Sakuraba, Toshiro Sato, Nobuhiko Kamada, Mina Kitazume, Akira Sugita, Toshifumi Hibi
    Gastroenterology November 2009 (Vol. 137, Issue 5, Pages 1736-1745)

Gastroenterology
Volume 137, Issue 5 , Pages 1566-1570, November 2009

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