Abstract
T cell immunoglobulin and mucin-4 (TIM-4), mainly expressed on dendritic cells (DC) and macrophages, plays an essential role in regulating immune responses. Langerhans cells (LC), which are the sole DC subpopulation residing at the epidermis, are potent mediators of immune surveillance and tolerance. However, the significance of TIM-4 on epidermal LCs, along with other cutaneous DCs, remains totally unexplored. For the first time, we discovered that epidermal LCs expressed TIM-4 and displayed an increased level of TIM-4 expression upon migration. We also found that dermal CD207+ DCs and lymph node (LN) resident CD207−CD4+ DCs highly expressed TIM-4, while dermal CD207− DCs and LN CD207−CD4− DCs had limited TIM-4 expressions. Using TIM-4-deficient mice, we further demonstrated that loss of TIM-4 significantly upregulated the frequencies of epidermal LCs and LN resident CD207−CD4+ DCs. In spite of this, the epidermal LCs of TIM-4-deficient mice displayed normal phagocytic and migratory abilities, comparable maturation status upon the stimulation as well as normal repopulation under the inflamed state. Moreover, lack of TIM-4 did not affect dinitrofluorobenzene-induced contact hypersensitivity response. In conclusion, our results indicated that TIM-4 was differentially expressed in the distinct subsets of DCs in skin and skin-draining LNs, and specifically regulated epidermal LC and LN CD207−CD4+ DC homeostasis.
Highlights
The T-cell immunoglobulin domain and mucin domain (TIM) family of genes, which contained eight members in mice and three members (Tim-1, Tim-3 and Tim-4) in human, was first positionally cloned in the T cell and airway phenotype regulator (Tapr) locus as a novel group of allergy and asthma susceptibility genes [1, 2]
While Langerhans cells (LC) represent the only dendritic cells (DC) subset within the epidermis, several DC subpopulations coexist in the steady-state dermis, including CD207+ DDCs, CD207-CD11b- DDCs, CD207-CD11b+ DDCs and LCs in transit, which are the migrated LCs enroute from the epidermis to nearby draining lymph node (LN) [39, 40]
The skin-draining LNs contain two major populations of DCs: One subset is migratory DCs, which include epidermal LCs and CD207+ DDCs; the other subpopulation is tissue-resident DCs, which encompass CD207+CD8+ DCs and a group of conventional CD207DCs subcategorized based on the expression of CD4 and CD8 [41,42,43]
Summary
The T-cell immunoglobulin domain and mucin domain (TIM) family of genes, which contained eight members (encoding TIM-1 to TIM-4 and putative TIM5 to TIM-8) in mice and three members (Tim-1, Tim-3 and Tim-4) in human, was first positionally cloned in the T cell and airway phenotype regulator (Tapr) locus as a novel group of allergy and asthma susceptibility genes [1, 2]. Previous studies emphasized a substantial role of the TIM family during various immune responses, including viral infection, allergy, autoimmunity, transplant tolerance and neoplasm immunity [3,4,5]. The in vivo functions of TIM-1 were manifold: high-affinity TIM-1-specific antibody enhanced T helper cell 1 (Th1) and Th17 responses, but hampered regulatory T cell (Treg) differentiation; low-affinity TIM-1 engagement promoted Th2 polarization with compromised T cell proliferation [6]. TIM-2 and TIM-3 preferentially enhanced Th2 differentiation and inhibited Th1 differentiation, respectively [7, 8]
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