**4.4 Pathogens regulate the CD4+ T cell differentiation process to establish chronic infections in cattle**

In addition to regulating activation signals, during the course of infection, pathogens can also regulate CD4+ T cell differentiation to evade the effective immune response mounted by the host. As already explained, intracellular pathogens can shift effective Th1 response to an ineffective Th2 response; similarly, extracellular pathogens can shift an effective Th2 response to an ineffective Th1 response, in order to promote the chronic infection in the host. For example, *S. japonicum* in mice can shift a Th2 response to an ineffective Th1 response by triggering apoptosis of Th2 cells via granzyme B signal pathway [248]. Similarly, some authors suggested that in chronic diseases such as bovine tuberculosis, immune complexes circulating in the blood might interfere specifically with Th1 response thus leading to a relatively increased Th2 response [249]. In cattle, intracellular pathogens including *Mycobacterium tuberculosis, Mycobacterium paratuberculosis and Bovine respiratory syncytial virus* (BRSV) shift the immune responses from a Th1 or a Th0 to an ineffective Th2 response, to establish chronic infections [128, 158]. In the same manner, extracellular pathogens such as *Dictyocaulus viviparus* modulate the immune response from a Th0 or a Th2 response to an ineffective Th1 response and establish the chronic infection [203, 204]. In summary, a fraction of bovine pathogens can skew the CD4+ T cell polarization to an ineffective subtype that cannot control their infection, which leads to the establishment of chronic infections.
