The Importance of Dendritic Cells in Asthma
The Importance of Dendritic Cells in Asthma
DCs work as the principal APCs in the immune system, but their function might vary according to their phenotype and the nature of signal they transduce to T-lymphocytes. DCs are found throughout the lung environment, starting from nose, nasopharynx, trachea, bronchi, bronchioles to alveoli. In human, various lung DCs survey antigen-rich areas to sample and uptake antigen. Endogenous antigens that are created intracellularly, including viral and tumor antigens, are processed by DCs and presented via MHC class I molecules to CD8 T-lymphocytes. Whereas, exogenous antigens, including bacterial antigens, pollen and other allergens, that are taken up through endocytosis or phagocytosis are presented via MHC class II molecules to polarize CD4 T helper lymphocytes.
While subtypes of human lung DCs are not yet completely understood, they can be divided into two major types: myeloid (conventional) and plasmacytoid DCs (Figure 1). Myeloid DCs (mDCs) can be further divided into two subtypes based on their surface markers. The mDCs are phenotypically CD11c/hi, BDCA1 (CD1c) and HLA-DR (MHC class II) or CD11c/int, BDCA3 (CD141) and HLA-DR. The second major phenotype of DCs is plasmacytoid DCs (pDCs) that can be divided into multiple subtypes, based on location and surface marker expression. Lung pDCs are CD123 (IL-3 receptor), CD11c, BDCA2 (CD303), BDCA4 (CD304), HLA-DR and ILT7 (CD85g) (Figure 1). Another subtype of pDCs has been found in tonsils and tumors with the expression of CD2. Its ability to secrete high levels of IL-12p40, and express high levels of co-stimulatory molecules, including CD80, postulates its role in antigen presentation to T-lymphocytes. However, role of CD2 pDCs in tolerance is yet to be established.
(Enlarge Image)
Figure 1.
Classification of mouse and human lung dendritic cells. Lung DCs in mouse and human are characterized by the presence of different epitopes. Their location and function vary depending upon their respective protein expression. DC: Dendritic cell.
Mouse DCs have similar subsets, but their localization and function is known far better than their human counterparts (Figure 1). Type I mDCs in mice express mucosal integrin, CD103, CD11c, CD11b, langerin (CD207) and CD24. They are close to the CD8α splenic DCs. These DCs are usually found above the basement membrane of tracheal epithelium. The main function of these mDCs is to take up the antigens and transfer them to lymph node DCs for communicating with CD4 T-lymphocytes. On the other hand, type II mDCs in mice are CD103, CD11b and CD11c, and express sialoglycoprotein, CD24. Phenotypically, they resemble the CD8α splenic DCs. They are found under the basement membrane of submucosa, and are major APCs in the uptake and processing of the antigens to prime and stimulate CD4 T-lymphocytes. Type II mDCs have huge amounts of TNF-α to support the T-lymphocytes, and CCL17 to attract Th2 and CD8 cytotoxic T-cells. Although, there is some ambiguity if these mDCs are involved in tolerance, it is evident from multiple findings that pDCs play a major role in the development of tolerance. Mice pDCs have B-cell-specific receptor B220 (CD45R) and express Ly6C, Siglec-H and mPDCA-1 (BST2). They reside under the basement membrane of trachea and alveolar septum. As pDCs have huge IFN-α levels, they can oppose the Th2 response and thus help in the regulation of allergic responses. However, the anti-Th2 response is not because of tolerogenic expansion of Tregs. In RNA virus infection, DCs (mDCs and pDCs) secrete IL-6 and IFN-α to induce antiviral response, which limits proliferation of Foxp3 Treg cells. Recently, lung pDCs have been subdivided into three populations based on the expression of CD8α and CD8β. Lombardi et al. demonstrated that CD8αβ pDCs contained immunogenic properties and expressed co-stimulatory molecules to support AHR, whereas CD8αβ CD8αβ showed tolerogenic properties and supported the development of Foxp3 Tregs in the presence of TGF-β and retinoic acid. Other groups have also tried to decipher subpopulations of pDCs with CCR9 (liver and bone marrow) and CD9 (tumor cells) as specific markers. However, immunogenic pDCs (CD8αβ), as well as tolerogenic pDCs (CD8αβ and CD8αβ) express comparable levels of CCR9, which is downregulated following TLR activation.
Plasmacytoid DCs directly help in the generation of Tregs through several pathways including secretion of immunosuppressive cytokines like indoleamine 2,3-dioxygenase (IDO), expression of programmed cell death ligand-1 (PD-L1) and retinoic acid. Presence of IL-10 during the differentiation of DCs helps in the development of tolerance. Myeloid DCs also take part in the induction of tolerance and CD103 mDCs in mesenteric lymph nodes might result in a tolerogenic response in the presence of TGF-β and retinoic acid. Multiple studies have shown that tolerogenic properties of DCs are usually linked to semi-mature DCs with high levels of MHC-II, but low levels of co-stimulatory molecules and pro-inflammatory cytokines. Identification of subtypes of DCs with immunogenic or tolerogenic potential in humans is crucial in designing interventional approach to control allergy and asthma. Better understanding of specific markers on DCs responsible for tolerance would help in developing better therapeutic strategies.
Phenotype of Dendritic Cells
DCs work as the principal APCs in the immune system, but their function might vary according to their phenotype and the nature of signal they transduce to T-lymphocytes. DCs are found throughout the lung environment, starting from nose, nasopharynx, trachea, bronchi, bronchioles to alveoli. In human, various lung DCs survey antigen-rich areas to sample and uptake antigen. Endogenous antigens that are created intracellularly, including viral and tumor antigens, are processed by DCs and presented via MHC class I molecules to CD8 T-lymphocytes. Whereas, exogenous antigens, including bacterial antigens, pollen and other allergens, that are taken up through endocytosis or phagocytosis are presented via MHC class II molecules to polarize CD4 T helper lymphocytes.
While subtypes of human lung DCs are not yet completely understood, they can be divided into two major types: myeloid (conventional) and plasmacytoid DCs (Figure 1). Myeloid DCs (mDCs) can be further divided into two subtypes based on their surface markers. The mDCs are phenotypically CD11c/hi, BDCA1 (CD1c) and HLA-DR (MHC class II) or CD11c/int, BDCA3 (CD141) and HLA-DR. The second major phenotype of DCs is plasmacytoid DCs (pDCs) that can be divided into multiple subtypes, based on location and surface marker expression. Lung pDCs are CD123 (IL-3 receptor), CD11c, BDCA2 (CD303), BDCA4 (CD304), HLA-DR and ILT7 (CD85g) (Figure 1). Another subtype of pDCs has been found in tonsils and tumors with the expression of CD2. Its ability to secrete high levels of IL-12p40, and express high levels of co-stimulatory molecules, including CD80, postulates its role in antigen presentation to T-lymphocytes. However, role of CD2 pDCs in tolerance is yet to be established.
(Enlarge Image)
Figure 1.
Classification of mouse and human lung dendritic cells. Lung DCs in mouse and human are characterized by the presence of different epitopes. Their location and function vary depending upon their respective protein expression. DC: Dendritic cell.
Mouse DCs have similar subsets, but their localization and function is known far better than their human counterparts (Figure 1). Type I mDCs in mice express mucosal integrin, CD103, CD11c, CD11b, langerin (CD207) and CD24. They are close to the CD8α splenic DCs. These DCs are usually found above the basement membrane of tracheal epithelium. The main function of these mDCs is to take up the antigens and transfer them to lymph node DCs for communicating with CD4 T-lymphocytes. On the other hand, type II mDCs in mice are CD103, CD11b and CD11c, and express sialoglycoprotein, CD24. Phenotypically, they resemble the CD8α splenic DCs. They are found under the basement membrane of submucosa, and are major APCs in the uptake and processing of the antigens to prime and stimulate CD4 T-lymphocytes. Type II mDCs have huge amounts of TNF-α to support the T-lymphocytes, and CCL17 to attract Th2 and CD8 cytotoxic T-cells. Although, there is some ambiguity if these mDCs are involved in tolerance, it is evident from multiple findings that pDCs play a major role in the development of tolerance. Mice pDCs have B-cell-specific receptor B220 (CD45R) and express Ly6C, Siglec-H and mPDCA-1 (BST2). They reside under the basement membrane of trachea and alveolar septum. As pDCs have huge IFN-α levels, they can oppose the Th2 response and thus help in the regulation of allergic responses. However, the anti-Th2 response is not because of tolerogenic expansion of Tregs. In RNA virus infection, DCs (mDCs and pDCs) secrete IL-6 and IFN-α to induce antiviral response, which limits proliferation of Foxp3 Treg cells. Recently, lung pDCs have been subdivided into three populations based on the expression of CD8α and CD8β. Lombardi et al. demonstrated that CD8αβ pDCs contained immunogenic properties and expressed co-stimulatory molecules to support AHR, whereas CD8αβ CD8αβ showed tolerogenic properties and supported the development of Foxp3 Tregs in the presence of TGF-β and retinoic acid. Other groups have also tried to decipher subpopulations of pDCs with CCR9 (liver and bone marrow) and CD9 (tumor cells) as specific markers. However, immunogenic pDCs (CD8αβ), as well as tolerogenic pDCs (CD8αβ and CD8αβ) express comparable levels of CCR9, which is downregulated following TLR activation.
Plasmacytoid DCs directly help in the generation of Tregs through several pathways including secretion of immunosuppressive cytokines like indoleamine 2,3-dioxygenase (IDO), expression of programmed cell death ligand-1 (PD-L1) and retinoic acid. Presence of IL-10 during the differentiation of DCs helps in the development of tolerance. Myeloid DCs also take part in the induction of tolerance and CD103 mDCs in mesenteric lymph nodes might result in a tolerogenic response in the presence of TGF-β and retinoic acid. Multiple studies have shown that tolerogenic properties of DCs are usually linked to semi-mature DCs with high levels of MHC-II, but low levels of co-stimulatory molecules and pro-inflammatory cytokines. Identification of subtypes of DCs with immunogenic or tolerogenic potential in humans is crucial in designing interventional approach to control allergy and asthma. Better understanding of specific markers on DCs responsible for tolerance would help in developing better therapeutic strategies.
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