ZAP-70, CTLA-4 and proximal T cell receptor signaling in cows infected with Mycobacterium avium subsp. paratuberculosis

Abstract

Paratuberculosis is a chronic intestinal disease of ruminant animals caused by Mycobacterium avium subsp. paratuberculosis (MAP). A hallmark of paratuberculosis is a transition from a cell-mediated Th1 type response to a humoral Th2 response with the progression of disease from a subclinical to clinical state. The objective of this study was to investigate the expression of two crucial molecules in T cell function, ZAP-70 (zeta-chain-associated protein of 70 kDa) and CTLA-4 (cytotoxic T-lymphocyte antigen-4), in cows naturally infected with MAP. Peripheral blood mononuclear cells (PBMCs) isolated from control non-infected cows (n=5), and cows in subclinical (n=6) and clinical stages of paratuberculosis (n=6) were cultured alone (medium only), and with concanavalin A, and a whole cell sonicate of MAP for 24, 72 and 144 h to measure the dynamic changes of ZAP-70 and CTLA-4 expression on CD4, CD8, and gamma delta (γδ) T cells. Flow cytometry was also performed to measure ZAP-70 phosphorylation to examine proximal T cell receptor signaling in animals of different disease status. The surface expression of CTLA-4 was increased in animals in subclinical stage of infection while levels of ZAP-70 were decreased in CD4+ T cells of both subclinical and clinical animals, indicating a change in T cell phenotype with disease state. Interestingly, proximal T cell receptor signaling was not altered in infected animals. This study demonstrated changes in crucial signaling molecules in animals infected with MAP, thereby elucidating T cell alterations associated with disease progression.

Bovine Immunoinhibitory Receptors Contribute to Suppression of Mycobacterium avium subsp. paratuberculosis-Specific T-Cell Responses

“…Accordingly, a recent study showed that CD4 ϩ T cells upregulated CTLA-4 in cattle during the subclinical stage of M. avium subsp. paratuberculosis infection (34).…”

Pathways and Genes Associated with Immune Dysfunction in Sheep Paratuberculosis

“…The primary aim of this study was to characterize the immune and inflammatory responses of M and P paratuberculosis in sheep, focussing on the nature of the immune dysfunction2128293031 associated with the M disease. TruSeq analysis was used to quantify transcripts expressed in the ICLN of diseased (M and P) and uninfected C animals.…”

“…Studies on the molecular nature of the reduced T cell function in bovine paratuberculosis have identified increased expression of immunoinhibitory molecules in the suppression of anti-MAP T cell responses in vitro 30, and shown a reduction in expression of the T cell receptor second messenger ZAP70 31.…”

The role of IL-10 in Mycobacterium avium subsp. paratuberculosis infection

“…The progression of paratuberculosis from subclinical to clinical form is mainly dependent on a gradual shift in immune response from a cell-mediated Th1 type response to a humoral Th2 response [16]. The naive helper T cells mainly differentiate into either Th1 cells or Th2 cells effecter cells after activation.…”

“…The hallmark of paratuberculosis is shift in immune response from a cell mediated Th1-type response to a humoral T helper2 (Th2) type response with the progression of disease from a subclinical to clinical phase [16]. Similarly, in ovine model of paratuberculosis, it is observed that the cellular immune response attenuates in natural and experimental MAP infected animals in more advanced phase of disease [17].…”