Calcitonin Gene-Related Peptide Biases Langerhans Cells toward Th2-Type Immunity

Abstract

Langerhans cells (LC) are epidermal dendritic cells capable, in several experimental systems, of Ag-presentation for stimulation of cell-mediated immunity. LC have been considered to play a key role in initiation of cutaneous immune responses. Additionally, administration of donor T cells to bone marrow chimeric mice with persistent host LC, but not mice whose LC have been replaced by donor cells, exhibit marked skin graft-vs-host disease, demonstrating that LC can trigger graft-vs-host disease. However, experiments with transgenic mice in which regulatory elements from human langerin were used to drive expression of diphtheria toxin, resulting in absence of LC, suggest that LC may serve to down-regulate cutaneous immunity. LC are associated with nerves containing the neuropeptide calcitonin gene-related peptide (CGRP), and CGRP inhibits LC Ag-presentation in several models including presentation to a Th1 clone. We now report that CGRP enhances LC function for stimulation of Th2 responses. CGRP exposure enhanced LC Ag presentation to a Th2 clone. Upon presentation of chicken OVA by LC to T cells from DO11.10 chicken OVA TCR transgenic mice, pretreatment with CGRP resulted in increased IL-4 production and decreased IFN-γ production. CGRP also inhibited stimulated production of the Th1 chemokines CXCL9 and CXCL10 but induced production of the Th2 chemokines CCL17 and CCL22 by a dendritic cell line and by freshly obtained LC. Changes in production of these chemokines correlated with the effect of CGRP on mRNA levels for these factors. Exposure of LC to nerve-derived CGRP in situ may polarize them toward favoring Th2-type immunity.

Calcitonin Gene-Related Peptide Is an Important Regulator of Cutaneous Immunity: Effect on Dendritic Cell and T Cell Functions

“…In LCs, CGRP regulates cellular functions such as cytokine production and Ag presentation in vitro (15). Ding et al (38) showed that CGRP treatment inhibited LC Ag presentation for a Th1 response but augmented Ag presentation for a Th2 response. They also showed that CGRP inhibits the production of the Th1-type chemokines CXCL9 and CXCL10 but induces the production of the Th2-type chemokines CCL17 and CCL22 in LCs (38).…”

“…Ding et al (38) showed that CGRP treatment inhibited LC Ag presentation for a Th1 response but augmented Ag presentation for a Th2 response. They also showed that CGRP inhibits the production of the Th1-type chemokines CXCL9 and CXCL10 but induces the production of the Th2-type chemokines CCL17 and CCL22 in LCs (38). These results suggest that CGRP has effects on dDCs similar to those observed on LCs, and that it inhibits Th1-type inflammatory responses such as TNCB-induced CHS.…”

Immunoregulatory Effects of Neuropeptides on Endothelial Cells: Relevance to Dermatological Disorders

“…Initially it was noted that CGRP inhibited antigen presentation for certain immune responses [47]. However, it was subsequently found that exposure of Langerhans cells to CGRP not only inhibits antigen presentation for Th1-type immunity; it enhances presentation for Th2 responses [48]. CGRP also inhibits the activation of nuclear factor-κB in human endothelial cells and the release of certain pro-inflammatory chemokines (IL-8, chemokine CCL2, chemokine CXCL1) in response to lipopolysaccharide [49], as well as increases the release of the inhibitory cytokine IL-10 from trigeminal glia [50] and macrophages [51].…”

“…In vitro, exposure of Langerhans cells to CGRP led to inhibition of antigen presentation for a Th1 response, while presentation for Th2 response was enhanced as evidenced by an increase in IL-4 (suppresses Th1 response) and decreased interferon-γ (supports Th1 response) [48]. Additionally, the stimulated production of Th1 chemokines CXCL9 and CXCL10 by Langerhans cells was reduced while the production of Th2 chemokines CCL17 and CCL22 was increased [48].…”

“…In vitro, exposure of Langerhans cells to CGRP led to inhibition of antigen presentation for a Th1 response, while presentation for Th2 response was enhanced as evidenced by an increase in IL-4 (suppresses Th1 response) and decreased interferon-γ (supports Th1 response) [48]. Additionally, the stimulated production of Th1 chemokines CXCL9 and CXCL10 by Langerhans cells was reduced while the production of Th2 chemokines CCL17 and CCL22 was increased [48]. These results are supported by a similar experiment in which receptor activity-modifying protein-1 knockout mice (this protein being a crucial component of the CGRP receptor) were used to support the finding that CGRP suppressed a Th1 contact hypersensitivity response, induced by the Th1 hapten sensitizer 2,4,6-trinitrochlorobenzene, and enhanced a Th2 contact hypersensitivity response, induced by the Th2 hapten sensitizer fluorescein isothiocyanate [52].…”