**4.3 Pathogens regulate the availability and the strength of three critical signals to suppress effective CD4+ T cell responses**

Whenever a pathogen invades and starts multiplying, the host mounts a coordinated attack in order to clear the infection. To counteract the host attacks, some pathogens can interfere with helper T cell responses to establish chronic infections. This can be achieved through unique strategies that impair the availability or strength of the signals required for the activation and differentiation of CD4+ T cells (**Figure 1**). For example, pathogens such as *Salmonella*, and *Mycobacterium tuberculosis* can downregulate MHC-II expression in APC, which diminishes the strength of the 1st signal (antigen stimulation) [233, 234]. In addition, pathogens can reduce the expression of co-stimulatory molecules (2nd signal) and change the type of APCs (*e.g.* dendritic cell vs. macrophage), which

can collectively impair all of the three signals required for the activation and differentiation of T cells (**Figure 1**) [235, 236].

Bovine pathogens escape from effective CD4+ T cell responses in a very similar way to those of mice and humans. They can regulate the availability, type, and strength of three signals. Some pathogens such as Bovine herpes virus type-1 (BHV-1), *Bovine papilloma virus (BPV)*, and *Mycobacterium paratuberculosis* can undermine the strength of antigen stimulation (1st signal) by downregulating MHC-I expression, which is actively involved in antigen presentation to CD8+ T cells [237–239]. Similarly, some pathogens can disrupt the host T cell response through inhibiting the co-stimulatory signals [211, 240, 241]. Co-stimulatory molecules expressed on the surface of CD4+ T cells (as shown in **Figure 1**) are of two types: one provides activating signals, and the other provides inhibiting signals [242]. Pathogens such as, *Bovine leukemia virus*, *Anaplasma marginale*, and *Fasciola hepatica* can upregulate the expression of inhibitory molecules like program cell death protein-1 (PD-1), which severely impairs the T cell response when these inhibitory molecules bind to their ligands on the surface of APCs [211, 240, 241]. Additionally, pathogens such as *Ostertagia ostertagi* and *Myctobacterium paratuberculosis* can induce immune-regulatory cytokines that can inhibit the activation, differentiation, and expansion of effector CD4+ T cell subtypes [26, 243, 244]. More specifically, *Ostertagia ostertagi* may stimulate neutrophils to produce IL-10, which can suppress bovine CD4+ T cell activation [26]. Furthermore, pathogens like *Fasciola hepatica* can reduce the number of APCs by apoptosis, which curtails the availability of all activating signals [211]. Moreover, pathogens such as *Anaplasma marginale, Bovine herpes virus − 1* and *Bovine viral diarrhea virus* can directly cause apoptosis of antigen-specific CD4+ T cell and starkly compromise the ability of the host to co-ordinate effective CD8+ T and antibody responses [241, 245–247]. In short, bovine pathogens regulate the CD4+ T cell responses by reducing the availability and strength of the three activating signals by changing the type and number of APCs, or by interfering with co-stimulation and cytokine production.
