Association of Marek’s Disease induced immunosuppression with activation of a novel regulatory T cells in chickens

Abstract

Marek’s Disease Virus (MDV) is an alphaherpesvirus that infects chickens, transforms CD4+ T cells and causes deadly lymphomas. In addition, MDV induces immunosuppression early during infection by inducing cell death of the infected lymphocytes, and potentially due to activation of regulatory T (Treg)-cells. Furthermore, immunosuppression also occurs during the transformation phase of the disease; however, it is still unknown how the disease can suppress immune response prior or after lymphoma formation. Here, we demonstrated that chicken TGF-beta+ Treg cells are found in different lymphoid tissues, with the highest levels found in the gut-associated lymphoid tissue (cecal tonsil: CT), fostering an immune-privileged microenvironment exerted by TGF-beta. Surprisingly, significantly higher frequencies of TGF-beta+ Treg cells are found in the spleens of MDV-susceptible chicken lines compared to the resistant line, suggesting an association between TGF-beta+ Treg cells and host susceptibility to lymphoma formation. Experimental infection with a virulent MDV elevated the levels of TGF-beta+ Treg cells in the lungs as early as 4 days post infection, and during the transformation phase of the disease in the spleens. In contrast to TGF-beta+ Treg cells, the levels of CD4+CD25+ T cells remained unchanged during the infection and transformation phase of the disease. Furthermore, our results demonstrate that the induction of TGF-beta+ Treg cells is associated with pathogenesis of the disease, as the vaccine strain of MDV did not induce TGF-beta+ Treg cells. Similar to human haematopoietic malignant cells, MDV-induced lymphoma cells expressed high levels of TGF-beta but very low levels of TGF-beta receptor I and II genes. The results confirm that COX-2/ PGE2 pathway is involved in immunosuppression induced by MDV-lymphoma cells. Taken together, our results revealed a novel TGF-beta+ Treg subset in chickens that is activated during MDV infection and tumour formation.

Synergistic Viral Replication of Marek’s Disease Virus and Avian Leukosis Virus Subgroup J is Responsible for the Enhanced Pathogenicity in the Superinfection of Chickens

“…Increased IL-10 might partly explain its pathogenic role in immunosuppression. Gurung [ 49 ] revealed a novel TGF-β Treg subset in chickens that is activated during MDV infection and tumor formation.…”

The effects of in ovo administration of encapsulated Toll-like receptor 21 ligand as an adjuvant with Marek’s disease vaccine

“…Generally, MDV life cycle can be divided into the cytolytic phase (2–7 days post-infection - dpi), latent phase (7–10 dpi), late cytolytic phase, and transformation phase 2 . Lysis of lymphocytes and activation of TGF-beta + regulatory T cells are a few mechanisms among others which induce immunosuppression during MDV infection 4 . Furthermore, transformed T cells proliferate form lymphoma which can lead to immunosuppression and clinical and pathological signs of disease.…”

The Emergence of a vv + MDV Can Break through the Protections Provided by the Current Vaccines

“…The sequences of specific primers and accession numbers for PD-1, PD-L1 and the chicken β-actin are listed in Table 2 [31]. The amplification program was as follows: 95 • C for 180 s, 45 cycles at 95 • C for 10 s, 60 • C for 30 s, followed by 95 • C 4.4 • C /s 10 s, 65 • C 2.2 • C /s 60 s. Each sample was tested in duplicate, and the data are presented as averages.Relative quantification of the genes was determined using the 2 −∆∆CT method[32].…”