Mycobacterium tuberculosis (Mtb) is one of the most important pathogens infecting humans. Although the immune response to Mtb has been extensively investigated, generation of an effective vaccine has been frustratingly difficult. Our laboratory, working in collaboration with the SKI laboratory of Michael Glickman, has generated CD4 T cell receptor transgenic mice specific for the immunodominant ESAT-6 epitope of Mtb and we are using these mice to identify the mechanisms by which CD4 T cells confer protection against infection. We are using adoptive T cell transfer to determine the effector mechanisms that CD4 T cells must express in order to optimally clear Mtb infection. The impact of inflammatory monocytes on in vivo Mtb growth and the role of monocytes in CD4 T cell priming, trafficking and differentiation are also being investigated.