Cellular Immune Suppressor Activity Resides in Lymphocyte Cell Clusters Adjacent to Granulomata in Human Coccidioidomycosis

Abstract

The in situ immunologic response in human coccidioidomycosis remains undefined. To explore this further, pulmonary necrotizing coccidioidal granulomata were examined using immunohistochemical staining for lymphocyte subsets and for the cytokines interleukin-10 (IL-10) and gamma interferon (IFN-␥). Discrete perigranulomatous lymphocytic clusters were seen in eight of nine tissues examined. In these tissues, T lymphocytes (CD3 ؉ ) significantly outnumbered B lymphocytes (CD20 ؉ ) in the mantle area of the granulomata (P ‫؍‬ 0.028), whereas the clusters were composed of roughly equal numbers of T and B lymphocytes. While the number of cells in the mantle expressing IL-10 was similar to those in the perigranulomatous clusters, there were significantly more cells expressing IFN-␥ in the mantle than in the clusters (P ‫؍‬ 0.037). Confocal microscopy revealed that CD4؉ T lymphocytes and B lymphocytes are associated with IL-10 production. CD4؉ CD25 ؉ T lymphocytes were identified in the perigranulomatous clusters but were not associated with IL-10 production. This is the first report noting perigranulomatous lymphocyte clusters and IL-10 in association with human coccidioidal granulomata and suggests that down-regulation of the cellular immune response is occurring within coccidioidal granulomata.Coccidioidomycosis is a fungal infection of increasing importance in the southwest United States (4). In the vast majority of cases, infection is acquired by inhalation of the fungus. Two-thirds of individuals who become infected are asymptomatic, their only evidence of infection being the expression of delayed-type hypersensitivity in response to a coccidioidal skin test. A variety of studies have indicated that protective immunity in human coccidioidomycosis is associated with an appropriate cellular immune response. Smith and colleagues demonstrated that persistent expression of delayed-type hypersensitivity presaged a good outcome, while failure to develop this response was associated with disseminated disease (20). More recently, in vitro studies have shown that peripheral blood T lymphocytes from individuals with well-controlled infection produce gamma interferon (IFN-␥) in response to coccidioidal antigen, while cells from individuals with disseminated disease do not (1). Failure of T lymphocytes to react to coccidioidal antigen in vitro is associated with a poorer clinical score among those with disseminated disease (2).The hallmark of a robust T-lymphocyte response is the granuloma (10), and the formation of necrotizing granulomata as a response to pulmonary coccidioidomycosis has long been associated with a strong cellular immune response and control of coccidioidal disease (6). However, the precise immunological events associated with this response have been largely unexplored. Modlin and colleagues, in work published in 1985 (13), described a distinct pattern of cellular response in a single human pulmonary granuloma. In this pattern, CD4 ϩ lymphocytes were dispersed throughout the granuloma, while CD8 ϩ lymphocytes...

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