HIV-Associated Cryptococcal Immune Reconstitution Inflammatory Syndrome is Associated with Aberrant T Cell Function and Increased Cytokine Responses

Abstract

Cryptococcal meningitis remains a significant opportunistic infection among HIV-infected patients, contributing 15%-20% of HIV-related mortality. A complication of initiating Antiretroviral therapy (ART) following opportunistic infection is Immune Reconstitution Inflammatory Syndrome (IRIS). IRIS afflicts 10-30% of HIV-infected patients with cryptococcal meningitis (CM), but its immunopathogenesis is poorly understood. We compared circulating T cell memory subsets and cytokine responses among 17 HIV-infected Ugandans with CM: 11 with and 6 without CM-IRIS. At meningitis diagnosis, stimulation with cryptococcal capsule component, glucuronoxylomannan (GXM) elicited consistently lower frequencies of CD4+ and CD8+ T cell memory subsets expressing intracellular cytokines (IL-2, IFN-γ and IL-17) among subjects who subsequently developed CM-IRIS. After ART initiation, T cells evolved to show a decreased CD8+ central memory phenotype. At the onset of CM-IRIS, stimulation more frequently generated polyfunctional IL-2+/IL-17+ CD4+ T cells in patients with CM-IRIS. Moreover, CD8+ central and effector memory T cells from CM-IRIS subjects also demonstrated more robust IL-2 responses to antigenic stimulation vs. controls. Thus, ART during CM elicits distinct differences in T cell cytokine production in response to cryptococcal antigens both prior to and during the development of IRIS, suggesting an immunologic foundation for the development of this morbid complication of CM infection.

T cell responses to control fungal infection in an immunological memory lens

“…In contrast, their defective expression led to higher mortality ( 160 ), suggesting an importance of type I immunity. Lower frequency of cytokine-producing memory CD8 + and CD4 + T cells was found in HIV-infected patients with Cryptococcus meningitis (CM), but their numbers were increased with more polyfunctional IL-2 + /IL-17 + CD4 + T cells and IL-2 + CD8 + T cells following antiretroviral therapy (ART) in CM-associated immune reconstitution inflammatory syndrome (CM-IRIS) ( 161 ) patients, suggesting the pathological role of cryptococcal memory T cells under certain conditions.…”

Cryptococcal Immune Reconstitution Inflammatory Syndrome: From Blood and Cerebrospinal Fluid Biomarkers to Treatment Approaches

“…Excessive expression of chemokines and integrins in peripheral blood precedes CM-IRIS and can be assessed by monitoring patients for pathological immune reconstitution [28]. Plasma levels of cytokines, such as IL-6, IL-18, TNF-α, IL-5, IFN-, IL-7, IL-17, GM-CSF, CCL11, and CXCL10 are also increased in patients who develop CM-IRIS [82][83][84]. The association between cytokines and CM-IRIS reflects a systemic immune response to events that occur in the central nervous system (CNS) [84].…”

“…Additionally, CXCR7 has recently been proposed as a potential therapeutic target receptor on CD14+CD16+ monocytes to limit neuroinflammation by controlling activated patrolling monocyte entry to CNS [85]. populations, which confer the inability to clear Cryptococcal antigens [82,86]. Peripheral blood from patients who had fatal outcomes revealed low GXM-and LPS-driven monocyte responses (CD16 +/-HLA-DR low ), reduced TNF-α, but increased IL-6, IL-10, CXCL10 production [86].…”

Immune Reconstitution Disorders: Spotlight on Interferons

“…Primary immunodeficiency state, driven by CD4+ T cell loss, results in severe impairment of all branches of the immune system. In immunocompromised patients with CD4+ T cell count <50 cells/uL, low T cell responses, as evidenced by low production of IFNG, IL8, IL6, and TNFA, leads to inefficient cytotoxic response, macrophage activation and pathogen clearance [ 117 ].…”