Primary Role for CD4⁺T Lymphocytes in Recovery from Oropharyngeal Candidiasis

Abstract

Oropharyngeal candidiasis is associated with defects in cell-mediated immunity and is commonly seen in human immunodeficiency virus positive individuals and AIDS patients. A model for oral candidiasis in T-cell-deficient BALB/c and CBA/CaH nu/nu mice was established. After inoculation with 10 8 Candida albicans yeasts, these mice displayed increased levels of oral colonization compared to euthymic control mice and developed a chronic oropharyngeal infection. Histopathological examination of nu/nu oral tissues revealed extensive hyphae penetrating the epithelium, with polymorphonuclear leukocyte microabscess formation. Adoptive transfer of either naive or immune lymphocytes into immunodeficient mice resulted in the recovery of these animals from the oral infection. Reconstitution of immunodeficient mice with naive CD4؉ but not CD8 ؉ T cells significantly decreased oral colonization compared to controls. Interleukin-12 and gamma interferon were detected in the draining lymph nodes of immunodeficient mice following reconstitution with naive lymphocytes. This study demonstrates the direct requirement for T lymphocytes in recovery from oral candidiasis and suggests that this is associated with the production of cytokines by CD4 ؉ T helper cells.

Bone marrow colony-formation in vitro after infection of genetically defined inbred mice with Candida albicans

“…The athymic nude mouse is deficient in T-lymphocyte number and function, and is highly susceptible to oral [3], but not to systemic [18][19][20] Candida infection. We postulated that the increased severity of oral infection in nude mice might place a greater strain on the innate effector mechanisms, and thus reveal quantitative differences in CFC production by the bone marrow.…”

“…Oral infection in nude mice reaches a peak at day 6, after which it remains relatively constant [3]. In the following experiments, assays at day 6 are referred to as acute infection, whereas assays late in the course of infection (day 56) are referred to as chronic infection.…”

“…Evidence to date suggests that recovery from infection is determined by cellmediated immune responses, acting via cytokine enhancement of the candidacidal activities of phagocytic cells [1]. Both clinical observations [2] and experimental models [3] indicate that defective cell-mediated immune responses predispose to oro-pharyngeal candidiasis; however, susceptibility to systemic disease is often associated with a dysfunctional response of neutrophils or mononuclear phagocytes [4,5].…”

“…Reconstitution of radiation chimeras with bone marrow from mice that developed 'high' or 'low' pathology was shown to determine the severity of tissue lesions after systemic challenge [14], suggesting that there were strain-dependent differences in the properties or production of the phagocytic effector cells recruited to the site of infection. These differences are genetically determined [15], are expressed in both systemic [13] and oral [3] infection, and appear to be related to some aspect of neutrophil number or function [16]. This parallels the human situation, in which Candida infections are commonly associated with neutropenia [17], or congenital defects that affect neutrophil function [5].…”

“…Since immunodeficient 'nude' mice are highly susceptible to oral infection [3], the analysis was extended to an examination of colony-forming responses in both acutely and chronically infected nude mice, and in nude mice restored to immunocompetence by reconstitution with syngeneic lymphocytes [3].…”