While immunogenic action of langerhans cells had thoroughly

While immunogenic action of langerhans pim inhibitor had thoroughly been illustrated, their tolerogenic action is still being in its infancy stage. Ralph. M. Steinman shared the Nobel Prize in 2011 for his work on dendritic cells and their role in immunity. He uncovered the role of dendritic cells in peripheral tolerance by applying antigen in absence of danger signal [12] the work that gave the second wing for dendritic cells and opened the door to know their role in homeostasis of the immune system. Julien Seneschal et al. (2012) illustrated the role of langerhans cells in maintaining immune homeostasis of the skin. The results emphasize that langerhans cells induce the proliferation of CD4+ CD25+FoxP3+CD127− skin resident regulatory T cells which located in the epidermis. These cells suppress autoreactive effector memory T cells by cell to cell contact. However, langerhans dendritic cells induce also expansion of skin resident-effector memory T cells when they are co-cultured with Candida albicans. So, Julien et al. suggested that under steady state condition langerhans cells can keep peripheral tolerance but they can also activate effector cells against danger signals [13]. But, although many researches were carried out in this field, It is remain to know in accurate how to constantly programming tolerogenic langerhans dendritic cells.
Regulatory T cells populations in the skin In the skin, there are skin resident memory T cells with general marker (CLA+,CD45O+,CCR4+) 20 times more than in blood [13,14], resident memory (CD4+CD25+FOXP3+ CD127−) regulatory T cells constitute 5% of these cells [15]. They are antigen specific and expanded by Langerhans dendritic cells which occur side by side with skin resident CD45O+ effector memory cells [13]. Beside skin resident memory T cells, skin dendritic cells specially langerhans cells present antigen to naïve T cells in draining lymph nodes. Activated T cells resulted from antigen presentation got either effector resident T cell markers (CCR4+, CLA+) or of central memory T cell markers (CCR7, L-selectin) [11]Fig. 1. Other type of Tregs are raised up in thymus by the process of negative selection, in which T cells that recognize self-antigens by T Cell Receptor with high affinity either died or selected to survive as Tregs. This type of Tregs is called natural Tregs and they are part of central tolerance, however some T cells escape this process and may cause autoimmunity [16]. It was suggested that loss of peripheral tolerance in the skin occurred in two steps: first, the induction phase in which the effector-autoreactive T cells were stimulated and expanded by CD4+ T cells. These cells circulate in the blood but with no symptoms of autoimmunity whereas in the effector phase the skin microenvironment became favor for escaping peripheral tolerance [17] as in autoimmune microenvironment of non-segmental vitiligo lesions in which down regulation of CCL22 expression causes reduction in skin homing by functional Tregs and resulted in imbalance between effector and regulatory mechanisms [18]. According to their sources, the Tregs are either natural Tregs or inducible Tregs. They both are FoxP3+ but were differentiated by neuropilin-1 (Nrp-1), which is selectively expressed on the surface of natural Tregs [19].
Major factors that regulate CCL22 Dendritic cells sense the antigens through various Pattern recognition receptors (PRR) expressed by dendritic cells. In response to this interaction, many cytokines and chemokines are secreted. In 2001 Vulcano M. et al. revealed the great role played by dendritic cells as the main source of CCL22 and stated different factors that regulate their expression summarized in Fig. 2. However in general, CCL22 is up regulated by cyclic AMP- elevating agents.
Model for study: non-segmental vitiligo In vitiligo, the melanocytes antigens are carried by langerhans dendritic cells and presented to naïve T cells in the draining lymph nodes. The circulating cutaneous lymphocyte antigen (CLA)-positive T cells are circulating memory cells in the blood and have T cell receptors (TCRs) specific to antigens of melanocytes previously encountered in the lymph nodes such as: A2-melanA tetramere + CTLs isolated from vitiligo patients expressed high levels of CLA [17].