**2.1 Th1 cells coordinate CD8+ T cell response to intracellular pathogens**

During the infection, the host responds to the intracellular pathogens by inducing cytokines such as IFNγ and IL-12 from APCs like macrophages and dendritic cells (DCs), which further leads to the polarization of CD4+ T cells into a Th1 subtype. IFNγ and IL-12 enhance the expression of transcription factor T-bet, which directs Th1 differentiation in the activated naïve CD4+ T cells (**Figure 2a**) [51, 52]. More specifically, when bound to their receptors on naïve CD4+ T cells, these cytokines induce the activation of transcription factor STAT-1 or STAT-4 respectively, which in turn causes T-bet upregulation [53]. Subsequently, T-bet induces histone modification and binds to the promoter region of Th1-specific cytokine genes, which leads to enhanced expression of IFNγ [51, 52]. In addition, T-bet also inhibits Th2 differentiation by repressing the transcription of Th2 specific genes, such as *GATA-3,* which is the transcription factor responsible for IL-4 expression [51, 54]. Thus, IFNγ and IL-12 induce Th1 differentiation, which leads to IFNγ production and suppression of Th2 differentiation.

One key functions of differentiated Th1 cells is to facilitate the activation of CD8+ T cells by "conditioning" dendritic cells; a process that induces dendritic cell (DC) maturation by modifying their cytoskeletal structure, upregulating co-stimulatory molecules, and by enhancing their migration to secondary lymphoid tissues [55–57]. Once conditioned, these DCs can induce CD8+ T cell activation as shown in **Figure 2(b)**. Although these two processes, conditioning of DCs and activation of CD8+ T cells, might occur simultaneously, some researchers argue that this process may occur in two sequential steps: conditioning DC first, followed by CD8+ T cell activation [56, 58, 59]. Activated CD8+ T cell secretes cytotoxicity-related proteins such as perforin and granzyme-B. While perforin forms pores at the cell membrane, granzyme enters through these pores and cause apoptosis of the infected cell [60]. Additionally, antigen-specific CD8+ T cells can kill infected cells through caspase mediated pathway, when Fas molecules expressed on the infected cells interact with Fas Ligand expressed on the antigen-specific CD8+ T cells [61].

IFNγ is a critical cytokine performing multiple functions to assist Th1 response against intracellular pathogens in mice, humans and cattle [62]. Although many types of immune cells can produce IFNγ including NK cells, DCs, macrophages and B cells, it is the signature cytokine of Th1 subtype [27]. Th1 produced IFNγ plays a critical role in regulating the Th1 response. IFNγ can recruit immune cells to the site of infection and promote anti-microbial activities of neutrophils and macrophages by inducing oxidative burst and production of reactive oxygen species (ROS) [62–65].

### **Figure 2.**

*Th1 help to the activation of CD8+ T cell. A) IFN*γ *and IL-12 bind to their corresponding receptors on naïve CD4+ T cells during activation, which leads to T-bet expression and Th1 differentiation. This figure was adapted from previous reviews [45–47]. B) Once differentiated, Th1 effector cell conditions dendritic cell, which in turn activates CD8+ T cell. This figure was adapted from previous reviews [48–50].*

### *CD4+ T Cell Responses to Pathogens in Cattle DOI: http://dx.doi.org/10.5772/intechopen.100410*

IFNγ is directly involved in blocking viral replication, as well as enhancing the cytotoxic activity of CD8+ T cells [66, 67]. Moreover, IFNγ can enhance the number, mobility, and cytotoxicity of CD8+ T cells [67, 68].

During infection caused by intracellular pathogens, Th1 produced IFNγ can induce IgG subtype switching in activated B cells. However, this subtype switching may differ among the species. For example, it induces production of IgG2a in mice and IgG2 in cattle but IgG1 and IgG3 in humans (**Table 1**) [18, 69, 73]. These IgG subtypes induced by IFNγ can facilitate multiple mechanisms such as ADCC to kill intracellular pathogens, such as *Coxiella burnetii, Listeria monocytogenes,* and *Toxoplasma gondii* in mice [19, 82].
