Chemokine receptor 1 knockout abrogates natural killer cell recruitment and impairs type-1 cytokines in lymphoid tissue during pulmonary granuloma formation

Mice with targeted mutation of chemokine receptor 1 (CCR1) were used to ass ess the contribution of CCR1 agonists to local, regional, and systemic infl ammatory-related events during experimental pulmonary granuloma formation. Models of Th1 (type-1) and Th2 (type-2) cell-mediated. lung granulomas were induced in wild-type (CCR+/+) and knockout (CCR1-/-) mice by embolizing Se pharose beads coupled to the purified protein derivative of Mycobacterium b ovis or soluble antigens derived, from Schistosoma mansoni eggs. Morphometr ic analysis indicated that granuloma sizes were unchanged in CCR1-/- mice, but now cytometric analyses of dispersed granulomas revealed that natural k iller cell recruitment to type-1 lesions was abrogated by 60%. Analysis of cytokine production by draining lymph node cultures showed altered expressi on in CCR1-/- mice characterized by reduced interleukin-2 and interferon-ga mma in the type-1 response, and enhanced interleukin-5 and interleukin-13 i n the type-2 response. Peripheral blood leukocytosis was also enhanced in t he type-1 but not the type-2 response. These findings suggest that CCR1 ago nists contribute to multiple immunoinflammatory events in the type-1 granul omatous response with natural killer cell accumulation being particularly s ensitive to CCR1 disruption. Although functional efficacy of granulomas may be altered, chemokine redundancy and cytokine reserve seem to make the bul k of the exudative response resistant to CCR1 disruption.