For Better or for Worse: The Influence of NK Cells, IFN-y and IL-4 on the Development of Protective Adaptive Immunity in Mycoplasma Respiratory Disease

Sheetal Bodhankar, For better or for worse: The influence of NK cells, IFN-y and IL-4 on the generation of protective adaptive immunity in mycoplasma respiratory disease, Doctor of Philosophy (Microbiology and Immunology) August 2008, 136 pp., 13 illustrations, 3 tables, bibliography, 176 titles. The purpose of these studies was to evaluate the contribution of NK cells and the polarizing cytokines, IFN-y and IL-4, in the generation of protective adaptive immunity against mycoplasma infection. Presence of NK cells during the generation of adaptive immunity resulted in detrimental immune responses. However, upon depletion of NK cells, prior to nasal-pulmonary immunizations, mice demonstrated better clearance of mycoplasma from the respiratory tracts. That the NK cells hindered with the beneficial development of adaptive immune responses via lymphoid cells was demonstrated, since no protection was demonstrated in SCID mice. Furthermore, purified pulmonary T and B lymphocytes primed in a NK cell depleted environment as opposed to one’s primed in a versus non-depleted environment could transfer protection to naïve mice. Interestingly, this is the first time that a favorable role of functional CD4 T cells in mediating protection in mycoplasma respiratory disease was demonstrated. The presence of NK cells at the time of nasal-pulmonary immunization also modulated mycoplasma-specific IFN-y and IL-4 responses in lungs and lower respiratory nodes. In evaluating the roles of IFN-y and IL-4, it was demonstrated that the absence of a single cytokine alters a vast array of chemokines and cytokines produced in response to mycoplasma infection. Corresponding to the higher numbers of mycoplasma and severity in disease due to the loss of IFN-y, altered cytokine and chemokine responses in the lungs to mycoplasma infection were demonstrated. Nasal-pulmonary immunization of IFN-y mice exacerbated, rather than reduced, mycoplasma disease and infection, whereas immunization of IL-4 mice significantly enhanced protection along the respiratory tract particularly in the lungs. Prominent Th-2 type immune responses in the lungs of IFN-y mice corresponded to the severe immunopathologic reactions developed after mycoplasma infection and immunization. These studies demonstrated diverse but crucial functions for NK cells, IFN-y and IL-4 vital towards the development of protective adaptive immune responses against mycoplasma respiratory infection that will have a significant impact on future studies on respiratory immunology.