Table 1.
Preclinical and clinical studies on T cell co-stimulatory and co-inhibitory molecules of the Ig-SF.
| Molecule on APC | Receptor on T cell | Experimental model | Effects on AD | Related cytokines | Perspectives/limitations | Ref. |
|---|---|---|---|---|---|---|
| B7-CD28 subfamily | ||||||
| CD80/CD86 | CD28 | DNFB-treated mice | ↑ CD28/CD80/CD86 protein expression and positive cells | IL-8, IL-12, IL-23 | ▪ Few studies ▪ Anti-CTLA-4 might result in irAEs |
50 |
| ▪ DNFB-treated mice ▪ HLJDT treatment |
↓ CD28/CD80/CD86 protein expression and positive cells ↓Clinical score ↓Ear swelling |
50 | ||||
| Skin lesions of AD patients | ↑Expression of CD80/CD86 on LCs | 51, 52 | ||||
| Serum samples of AD patients | ↑Expression of CD28 autoantibodies | 53 | ||||
| ▪ PBMCs of AD patients ▪ Anti-CTLA-4 treatment |
↑Proliferation and IgE synthesis of PBMCs | 54 | ||||
| CTLA-4 | NC/Nga mice (application of mite antigens) | ↑CD80/CD86/CTLA4 gene expression in the skin | 55 | |||
| ▪ NC/Nga mice (application of mite antigens) ▪ La1 treatment |
↓CD80/CD86/CTLA-4 expression ↓Development of AD-like lesions ↓Skin score |
55 | ||||
| AD infants | CTLA-4 overexpression | 56 | ||||
| Peripheral blood of infants with moderate to severe AD | ↑CTLA-4 express on Tregs | 57, 58 | ||||
| PD-L1/PD-L2 | PD-1 | IL-4 transgenic mice | ↑PD-1 expression on CD4+ and CD8+ T cells | – | Block PD-1 or PD-L1 might result in irAEs | 59 |
| ▪ MC903-treated PD-L1-/- mice ▪ MC903-treated PD-L2-/- mice |
↑Ear swelling in PD-L1-/- mice ↑Ear swelling in PD-L2-/- mice |
60 | ||||
| ▪ NC/Nga mice ▪ PD-L2 siRNA treatment |
Ineffective | 61 | ||||
| PBMCs of infants with moderate to severe AD | ↑PD-1 expression on Tregs | 62 | ||||
| ▪ AD patients with disseminated Kaposi sarcoma ▪ Treatment with pembrolizumab |
AD improved | 63 | ||||
| CD28 subfamily | ||||||
| ICOS | ICOSL | VitD mouse model of AD | ↑Percentages of ICOS+ Tregs in sdLNs | IL-10 | Studies focus on Tregs | 64 |
| PBMCs of AD patients | ↑Percentages of ICOS+ Tregs ↓Production of IL‐10 |
65 | ||||
| PBMCs and lesional skin of Han Chinese population with AD | ↑ICOS+ Th22 ICOS+ Th22 and ICOSL+ B cells were related to disease activity and total serum IgE levels ↑Expression of ICOS and ICOSL expression in lesional skin |
66 | ||||
| DNA and blood samples of European children | None of the six evaluated ICOS gene variants was related to the development of allergic phenotypes | 67 | ||||
| HVEM | BTLA | ▪ CXCR5hiPD1hi CD4 naive T (Tfh characteristics) co-culture with TSLP-activated DCs ▪ AD donors |
↑BTLA protein and mRNA ↑Tfh in AD |
– | Need more studies | 68 |
| CD2/SLAM subfamily | ||||||
| CD58 | CD2 | PBMCs of AD patients in children | ↓CD2+ lymphocytes | IL-5, IL-10, IL-13, IFN-γ, GM-CSF | No biological targets currently | 69 |
| ▪ PBMCs of AD patients ▪ Anti-CD2-blocking mAb treatment |
↓INF-γ, GM-CSF, and IL-5 levels | 70 | ||||
| ▪ AD patients ▪ Treatment with alefacept |
Symptom improvement ↓Skin T cells ↓IL-5, IL-10, IL-13, IFN-γ |
71 | ||||
| CD48 | 2B4 | ▪ Eos of AD patients ▪ SA exotoxin treatment |
↑CD48+ Eos | – | Need more studies | 72 |
| 2B4-/- mice induced with 2-week OVA/SEB | ↑Eos trafficking | 73 | ||||
| 2B4-/- mice induced with 3-week OVA/SEB | ↑MC activation | 74 | ||||
| Peripheral T cells of AD patients | ↑2B4 gene expression | 75 | ||||
| SLAM | SLAM | ▪ Th2 cell populations derived from skin biopsies of AD patients ▪ Treatment with SLAM by an agonist mAb |
↑INF-γ-producing cells | IFN-γ | Reverse the Th cell phenotype of AD | 76 |
| CD226 subfamily | ||||||
| CD155 | TIGIT | PBMCs of AD patients | ↑TIGIT expression The proportion of TIGIT+ cells was correlated with AD severity The frequency of TIGIT+ cells in CD4+ T cells was negatively correlated with serum thymus and activation-regulated chemokine levels and lgE levels in AD patients |
– | Need more evidence on TIGIT functions | 77 |
| TIM subfamily | ||||||
| TIM4 | TIM1 | ▪ OVA-sensitized AD-like mouse model ▪ AD-like skin lesions of NC/Nga mice |
TIM4 expression on Langerhans-like DCs inhibited Th2 cell development and was beneficial for controlling AD | – | Need further research | 78–80 |
| Blood samples of AD patients | TIM1 exon 4 variations were associated with AD | 81 | ||||
| Australian Caucasian families and Asian families | A novel association between AD and the major haplotype of TIM4 Genetic variants in the ligand for TIM1 and TIM4 contributed to AD presentation |
82 | ||||
| Orphan subfamily | ||||||
| HVEM | CD160 | Skin lesions of AD patients | ↑CD160+ T cell infiltration The engagement of CD160 enhanced the CD4+CD160+ cell proliferation induced by CD3 stimulation |
– | Need experiments to elucidate the exact functions | 83 |
APC, antigen-presenting cell; CTLA4, cytotoxic T lymphocyte antigen 4; PD-1, programmed cell death 1; PD-L1/PD-L2, programmed cell death 1 ligand 1/2; ICOS, inducible T cell co-stimulator; ICOSL, ICOS ligand; BTLA, B and T lymphocyte attenuator; HVEM, herpesvirus entry mediator; SLAM, signaling lymphocyte activation molecule; TIM, T cell immunoglobulin and mucin domain.