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The Journal of Immunology, 2008, 180, 2772 -2776
Copyright © 2008 by The American Association of Immunologists, Inc.
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Cutting Edge: Vasoactive Intestinal Peptide (VIP) Induces Differentiation of Th17 Cells with a Distinctive Cytokine Profile1

Mahesh Yadav, Jennifer Rosenbaum and Edward J. Goetzl2

Department of Medicine and Department of Microbiology-Immunology, University of California Medical Center, San Francisco, CA 94143


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Immune cellular effects of vasoactive intestinal peptide (VIP) are transduced by VIP G protein-coupled receptors type 1 (VPAC1) and type 2 (VPAC2). We now show that VIP with TGFβ stimulates the transformation of CD4 T cells to a distinctive type of Th17 cell that generates IL-17 but not IL-6 or IL-21. VIP induction of Th17 cells was higher in VPAC2 knockout mice than wild-type mice, suggesting that VPAC1 is the principal transducer. Compared with Th17 cells elicited by IL-6, those evoked by VIP were similar in the secretion of IL-17 and IL-22, but lacked IL-21 secretion. Suppression of VIP induction of Th17 cells by protein kinase A inhibitors and enhancement by pharmacologically increased cAMP supports a role for this signal. The ability of VIP-VPAC1 axis signals to evoke development of a novel type of Th17 cells demonstrates the unique specificity of neuroregulatory mechanisms in the immunological environment.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Vasoactive intestinal peptide (VIP)3 is a 28-aa neuroendocrine mediator secreted by specific sets of neurons and T cells. VIP has major effects on diverse T cell functions, including differentiation, survival, migration, proliferation, and cytokine generation (1, 2). Two homologous G protein-coupled receptors, designated type 1 VIP receptor (VPAC1) and type 2 VIP receptor (VPAC2) bind VIP specifically with high affinity and transduce the effects of VIP on T cells. Resting T cells constitutively express VPAC1 but little VPAC2, and their activation reduces the level of VPAC1 and increases that of VPAC2 (3). Th2 cells are the principal source of VIP and express the highest level of VPAC receptors (2). High levels of VPAC2 in T cells of a transgenic mouse resulted in heightened immediate-type hypersensitivity and depressed delayed-type hypersensitivity due to an increased ratio of Th2-type cytokines to Th1-type cytokines. In contrast, an increased ratio of Th1-type cytokines to Th2-type cytokines in VPAC2-null mice led to enhanced delayed-type hypersensitivity and reduced immediate-type hypersensitivity (2, 4).

Many different T cell-directed activities of the VIP-VPAC receptor axes have been identified in autoimmune diseases (5). However, no studies have to date focused on Th17 cells, which recently have been recognized for their inflammatory effector activities in mouse models of autoimmunity (6, 7). This report describes the capacity of VIP-VPAC1 signals to induce the differentiation of CD4 T cells into a Th17 set in a TGFβ-rich environment free of IL-6. These novel VIP-induced Th17 cells are distinguished from those stimulated to differentiate with TGFβ plus IL-6 by their production of high levels of IL-17 and IL-22 without IL-21 or IL-6.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 Disclosures
 References
 
Mice and reagents

The VPAC2-null mice were created initially on a mixed C57BL/6 x 129ola genetic background and backcrossed on C57BL/6, as previously described (4). Murine IL-6 and TGFβ (Peprotech), murine IL-27 (eBioscience), Abs to murine CD3 and CD28 (referred to hereafter as "a-TCR") and rat IgG1 anti-mouse IL-17 (clone TC11-18H10.1) (BD Pharmingen), anti-CD126 (IL-6R {alpha}-chain) (BioLegend), Ro-20-1724, KT5720, H-89, and goat alkaline phosphatase-conjugated anti-rat IgG Ab and 5-bromo-4-chloro-3-indolyl phosphate/NBT alkaline phosphatase substrate (Calbiochem) were from the supplier indicated.

CD4 T cell isolation, culture, and activation

Mouse CD4 T cells were isolated from the splenocytes of 6- to 10-wk-old wild-type (WT) or VPAC2-null C57BL/6 mice by immunomagnetic bead positive selection (Miltenyi Biotec) and seeded in 48-well plates precoated with 0.5 µg each of a-TCR Abs. TGFβ (10 ng/ml), IL-6 (10 ng/ml), and/or IL-27 (100 ng/ml) were added at the start of the culture as described in the text. VIP was added to the cultures initially and every 24 h. The phosphodiesterase inhibitor Ro-20-1724 (5 and 20 µM) and the protein kinase A (PKA) inhibitors KT5720 (500 nM and 1 µM) and H-89 (200 nM) were added on 0 day at 20 min before the addition of VIP and cytokines.

Quantification of expression of VPAC1 receptor by mouse splenic CD4 cells

The mRNAs encoding mouse VPAC1 receptors and the mouse endogenous control hypoxanthine phosphoribosyltransferase were quantified in a Prism 9700 sequence detection system (Applied Biosystems) using primers and probes of published sequences (4). The value for each unknown was determined from its optimized threshold cycle (CT) and normalized with reference to the CT value of hypoxanthine phosphoribosyltransferase as described (4).

Quantification of cytokine production

IL-17, IL-22, IL-6 (Ready Set-Go kits; eBioscience), and IL-21 (R&D Systems) in all supernatants were quantified in duplicate with ELISA kits.

IL-17 ELISPOT Assay

Variously treated CD4 T cells were incubated for 2 h at 37°C in anti-CD3 Ab-coated 24-well plates for ELISPOT assays with a minimum total of 300 cells per well and counting as described previously (8).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Disclosures
 References
 
Equivalent stimulation of IL-17 induction by IL-6 and VIP in the presence of TGFβ

The previously reported capacity of TGFβ to initiate the conversion of anti-CD3 and anti-CD28 Ab (referred to throughout as "a-TCR")-activated CD4 T cells into Th17 cells was documented in this study by a >10-fold increase in production of IL-17 after 5 days of incubation with TGFβ (Fig. 1A). Concurrent introduction of 10–7 M VIP further enhanced the differentiation of Th17 cells by 3-fold to a level similar to that attained by costimulation with an optimal concentration of IL-6. VIP effects on Th17 induction occurred only in the presence of TGFβ and not with VIP alone or in combination with IL-6 (Fig. 1A and data not shown). Because VPAC1 vastly predominates over VPAC2 when CD4 T cells are exposed initially to VIP with TGFβ, we presumed that Th17 differentiation-enhancing signals are transduced by VPAC1. Further analysis of VPAC receptor involvement was pursued with the CD4 T cells of VPAC2-null mice that express a significantly higher level of mRNA encoding VPAC1 than do WT CD4 T cells in the absence of VPAC2 (Fig. 1B). The probability that VPAC1 is the principal transducer of the Th17-differentiating activity of VIP was supported by a significantly higher level of Th17 development from VPAC2-null than WT CD4 T cells without and with exogenous VIP in the absence of TGFβ (Fig. 1C and data not shown). Enhanced levels of IL-17 in VPAC2-null CD4 T cells compared with the WT T cells without exogenous VIP is the result of previously demonstrated endogenous VIP (2). With TGFβ costimulation for 5 days, 10–7 M VIP increased IL-17 generation significantly higher for VPAC2-null CD4 T cells than for the WT (Fig. 1C). Optimum differentiation of TGFβ-induced Th17 cells occurred at 10–7 to 10–6 M VIP (Fig. 1D). ELISPOT assays of intracellular IL-17 confirmed the equivalent differentiation-enhancing activities of VIP and IL-6. IL-17 was detected in 23 ± 2% (mean ± SD) of CD4 T cells with TGFβ alone and at significantly higher levels of 41 ± 4% and 35 ± 3%, respectively, with TGFβ plus VIP and TGFβ plus IL-6 (Fig. 1E). The peak enhancement of TGFβ-initiated differentiation of Th17 cells by 10–7 M VIP was achieved after 5 days and was a mean of 18 and 78% of this maximum at 3 and 4 days, respectively (Fig. 1F), and did not rise further after 7 days (data not shown).


Figure 1
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  		FIGURE 1. Alternative Th17 differentiation by the VIP-VPAC1 axis in TGFβ-stimulated splenic CD4 T cells. A, IL-17 production by WT splenic CD4 T cells in vitro after exposure to a-TCR Abs and stimulation with 10–7 M VIP, TGFβ, TGFβ plus IL-6, or TGFβ plus 10–7 M VIP. B, Relative expression of mRNA encoding VPAC1 analyzed using real-time PCR analysis in VPAC2-null or WT CD4 T cells stimulated with a-TCR. C, IL-17 secretion by a-TCR-stimulated VPAC2-null or WT CD4 T cells in response to TGFβ plus IL-6 or VIP at 5 days. D, IL-17 secretion by a-TCR-stimulated VPAC2-null CD4 T cells in the presence of TGFβ and different concentrations of VIP. E, Percentage of IL-17-producing cells in a-TCR-activated VPAC2-null CD4 T cells determined at 5 days using an ELISPOT assay. F, IL-17 secretion by a-TCR-stimulated VPAC2-null CD4 T cells exposed to TGFβ plus IL-6, TGFβ plus 10–7 M VIP, or TGFβ alone for different times. Each column and bar depict the mean ± SD of the results of three different studies in A, B, C, and E and are representative of one of the three experiments in D and F. The levels of statistical significance are as follows: *, significant to TGF alone; **, significant to 3 days; +, significant to WT; §, significant to 10–8 M VIP; calculations were by a two-tailed paired t test (p < 0.05).

 
The fact that the Th17-differentiating effect of VIP is not attributable to increased generation of IL-6 was demonstrated by a significant suppression of CD4 T cell secretion of IL-6 by VIP and TGFβ alone and in combination (Fig. 2) In addition, the blocking of endogenous T cell-derived IL-6 signaling by anti-IL-6R (receptor) Abs inhibited the optimum IL-17 generation induced by TGFβ plus IL-6 but not by TGFβ plus VIP (data not shown). VIP elicitation of Th17 differentiation also did not result from IFN-{gamma} suppression, because VPAC2-null CD4 T cell suspensions generate more IFN-{gamma} than do WT CD4 T cells and yield higher levels of Th17 cells. Further, VIP did not alter IFN-{gamma} production in TGFβ-stimulated CD4 T cells (data not shown). Many other factors serve as late stimuli of differentiation of Th17 cells such as IL-23, which evokes the expansion of previously differentiated Th17 populations (9, 10, 11, 12). Our current findings demonstrate that VIP acts as an early inducing mediator of Th17 differentiation in the presence of TGFβ in a manner similar to that of IL-6.


Figure 2
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  		FIGURE 2. TGFβ and VIP suppression of IL-6 generation by VPAC2-null CD4 T cells. Each column and bar depicts the mean ± SD IL-6 production in VPAC2-null splenic CD4 T cells stimulated with a-TCR Abs and treated with TGFβ and/or 10–7 M VIP (n = 3). The level of statistical significance is as follows: *, significant to TCR; calculated by a two-tailed paired t test (p < 0.05).

 
Distinctive cytokine profile of Th17 cells induced in the presence of VIP

Th17 cells differentiated by incubation with TGFβ plus IL-6 and TGFβ plus VIP exhibit different cytokine profiles. As for IL-17, Th17 cells of both types generated similar levels of IL-22 after a-TCR-mediated activation. Both VIP and IL-6 with TGFβ, but not VIP alone, enhanced the production of IL-22 by 5- to 7-fold (Fig. 3A), and the combination of TGFβ plus VIP and IL-6 additively enhanced IL-22 production.


Figure 3
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  		FIGURE 3. Distinct cytokine profile of Th17 cells stimulated with a-TCR and TGFβ plus VIP or TGFβ plus IL-6. A and B, Production of IL-22 (A), IL-17 (B, filled bars), or IL-21 (B, open bars) by splenic CD4 T cells from VPAC2-null mice that were stimulated with a-TCR with or without 10–7 M VIP and TGFβ or IL-6 or both. C and D, VPAC2-null CD4 T cells were exposed to a-TCR and triggered with TGFβ plus IL-6 or TGFβ plus VIP as described earlier in the presence of absence of IL-27. Cytokine concentrations in the culture supernatants were determined after 5 days using an ELISA. Each column and bar depicts mean ± SD of the results of three studies. The levels of statistical significance are as follows: *, significant to TCR; +, significant to without VIP in the group; **, significant to control; calculations were by a two-tailed paired t test (p < 0.05).

 
In sharp contrast, IL-6 but not VIP enhanced the generation of IL-21 by a-TCR Ab and TGFβ-activated CD4 T cells (Fig. 3B). Under conditions that evoked maximal production of IL-17, TGFβ plus IL-6 induced up to a 4-fold increase in the generation of IL-21 compared with the level attained by TGFβ alone. IL-6 alone elicited an increase in IL-21 generation similar in magnitude to that achieved by TGFβ plus IL-6 in the absence of any effect on IL-17 production. Neither VIP alone nor TGFβ plus VIP, which evoked maximal production of IL-17, induced CD4 T cells to produce any detectable IL-21 (Fig. 3B). The addition of VIP to TGFβ plus IL-6 and to IL-6 alone inhibited IL-21 generation by Th17 cells, suggesting selective inhibition of IL-21 induction by VIP. Th17 cells of both types are similar in their susceptibility to the effects of Th17 inhibitors. IL-27 suppressed the generation of IL-17 by Th17 cells from both sources without inhibiting IL-21 production in TGFβ plus IL-6-induction (Fig. 3, C and D).

A recently reported role for IL-21 in the stimulation of differentiation and proliferation of Th17 cells suggests that IL-21 first is up-regulated by IL-6 (13, 14). IL-21 then acts in an autocrine manner to further enhance Th17 differentiation, which was not observed in IL-21R–/– CD4 T cells (14). Thus, Th17 differentiation by TGFβ plus VIP, without the induction of IL-21, demonstrates an IL-21-independent alternative pathway for the development of Th17 cells. We also documented a distinctive Th17 cell cytokine profile in Th17 cells differentiated by VIP, as contrasted with IL-6. Another IL-21-independent difference observed between Th17 cells of the two types was the generation of IL-22 at levels similar to those for IL-17 when differentiation was stimulated by TGFβ plus VIP rather than TGFβ plus IL-6. Suppression of IL-17 but not IL-21 production by IL-27 suggests an inhibitory site downstream of the point of IL-6 stimulation of IL-21 production.

VIP-induced differentiation of Th17 cells is dependent on the cAMP/PKA pathway

VIP G protein-coupled receptors evoke cAMP production leading to the activation of PKA and ERK signals that mediate most of the immunological effects of VIP (5, 15, 16). To delineate the involvement of cAMP/PKA pathways in VIP effects on Th17 development, inhibitors of different points in the pathway were examined for their capacity to alter VIP induction of Th17 development. Inhibition of cAMP phosphodiesterase activity by Ro-20-1724 enhanced IL-17 generation by TGFβ-differentiated Th17 cells without any IL-21 production. This profile resembles what was observed in Th17 cells developing under the combined influence of TGFβ plus VIP (Fig. 4, A and B). Ro-20-1724 did not increase further IL-17 production in cells treated with TGFβ plus VIP (data not shown). The possibility that VIP induction of Th17 cells is mediated by increased intracellular concentrations of cAMP (16) was supported by the demonstration of significant suppression of Th17 differentiation induced by TGFβ plus VIP, but not by TGFβ plus IL-6, when optimal concentrations of the PKA inhibitors KT5720 and H-89 were added with the stimuli at the beginning of the incubation period (Fig. 4C). cAMP/PKA pathways appear to have a central role in the stimulating effects of VIP on Th17 development, but not in the induction by TGFβ plus IL-6.


Figure 4
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  		FIGURE 4. VIP induced IL-17 generation is dependent on cAMP/PKA pathways. A and B, VPAC2-null CD4 T cells were stimulated with a-TCR and TGFβ without and with 10–7 M VIP or IL-6 or the cAMP-specific phosphodiesterase inhibitor Ro-20-1724 (Ro) at 5 and 20 µM for 5 days. C, VPAC2-null CD4 T cells were stimulated with a-TCR and TGFβ plus IL-6 or 10–7 M VIP in the presence or absence of the PKA inhibitors KT5720 (at 500 nM and 1 µM) and H-89 (200 nM) for 5 days. The control values were 2087 ± 96 and 2673 ± 217 pg/ml for TGFβ plus IL-6 and TGFβ plus VIP, respectively. Each column and bar depicts mean ± SD of the results representative of three separate experiments. The levels of statistical significance are as follows: +, significant to TGF alone (p < 0.01); *, significant to control (p < 0.05); calculations were by a two-tailed paired t test.

 
Identification of a novel VIP-mediated alternative pathway in the development of Th17 advances one step further our understanding of how VIP alters the differentiation of different T cells subsets (2, 4, 17). Current evidence for a preferential role of the VIP-VPAC1 axis in Th17 differentiation exemplifies how the selective binding of VIP to the different receptors can induce differential T cell signaling. Thus, enhancement of the relative contribution of VIP-VPAC1 axis signaling can skew the CD4 T cell response toward a Th17-rich proinflammatory type. This hypothesis is supported by a recent study showing that activated CD4 T cells from human multiple sclerosis (MS) patients had reduced VPAC2 expression and unchanged VPAC1 expression compared with the controls, resulting in a Th cell response skewed to cell-mediated immune inflammation (18). Based on our results, it seems possible that the reduced VPAC2 expression in MS patients may result in a relatively increased level of VIP-VPAC1 signaling and thereby the generation of inflammatory Th17 cells and MS immunopathology. Down-regulation of IL-21 by VIP could also diminish differentiation and activation of NK cells whose cytotoxic activity is augmented in the presence of IL-21 (19, 20).

The expression of VIP-VPAC1 signaling provides an alternative mechanism for generating Th17 cell inflammatory responses in a low IL-6 or IL-21 environment. Ongoing exploration of roles of the VIP-VPAC2 axis in altering development of regulatory T cells and Th17 cells will provide more definitive overall understanding of the regulation and integration of these processes by VIP. Lastly, the development of selective and bioavailable drugs that increase or inhibit VPAC1 signals may permit more specific therapeutic intervention in infectious and autoimmune diseases.


   Disclosures
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 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by National Institutes of Health Grant R0-1 AI29912. Back

2 Address correspondence and reprint requests to Dr. Edward J. Goetzl, University of California, Room UB8B, UC Box 0711, 533 Parnassus at Fourth Avenue, San Francisco, CA 94143-0711. E-mail address: edward.goetzl{at}ucsf.edu Back

3 Abbreviations used in this paper: VIP, vasoactive intestinal peptide; a-TCR, anti-CD3 and anti-CD28 Ab; MS, multiple sclerosis; PKA, protein kinase A; VPAC1, VIP type 1 receptor; VPAC2, VIP type 2 receptor; WT, wild type. Back

Received for publication October 26, 2007. Accepted for publication January 15, 2008.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 

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