Soluble T cell immunoglobulin mucin domain 3 is shed from CD8+ T cells by the sheddase ADAM10, is increased in plasma during untreated HIV infection, and correlates with HIV disease progression.

UNLABELLED: Chronic HIV infection results in a loss of HIV-specific CD8(+) T cell effector function, termed "exhaustion," which is mediated, in part, by the membrane coinhibitory receptor T cell immunoglobulin mucin domain-3 (Tim-3). Like many other receptors, a soluble form of this protein has been described in human blood plasma. However, soluble Tim-3 (sTim-3) is poorly characterized, and its role in HIV disease is unknown. Here, we show that Tim-3 is shed from the surface of responding CD8(+) T cells by the matrix metalloproteinase ADAM10, producing a soluble form of the coinhibitory receptor. Despite previous reports in the mouse model, no alternatively spliced, soluble form of Tim-3 was observed in humans. Shed sTim-3 was found in human plasma and was significantly elevated during early and chronic untreated HIV infection, but it was not found differentially modulated in highly active antiretroviral therapy (HAART)-treated HIV-infected subjects or in elite controllers compared to HIV-uninfected subjects. Plasma sTim-3 levels were positively correlated with HIV load and negatively correlated with CD4 counts. Thus, plasma sTim-3 shedding correlated with HIV disease progression. Despite these correlations, we found that shedding Tim-3 did not improve the function of CD8(+) T cells in terms of gamma interferon production or prevent their apoptosis through galectin-9. Further characterization studies of sTim-3 function are needed to understand the contribution of sTim-3 in HIV disease pathogenesis, with implications for novel therapeutic interventions. IMPORTANCE: Despite the overall success of HAART in slowing the progression to AIDS in HIV-infected subjects, chronic immune activation and T cell exhaustion contribute to the eventual deterioration of the immune system. Understanding these processes will aid in the development of interventions and therapeutics to be used in combination with HAART to slow or reverse this deterioration. Here, we show that a soluble form of T cell exhaustion associated coinhibitory molecule 3, sTim-3, is shed from the surface of T cells. Furthermore, sTim-3 is elevated in the plasma of treatment-naive subjects with acute or chronic HIV infection and is associated with markers of disease progression. This is the first study to characterize sTim-3 in human plasma, its source, and mechanism of production. While it is still unclear whether sTim-3 contributes to HIV pathogenesis, sTim-3 may represent a new correlate of HIV disease progression.

T cell Ig and mucin domain-containing protein 3 is recruited to the immune synapse, disrupts stable synapse formation, and associates with receptor phosphatases.

CD8(+) CTLs are adept at killing virally infected cells and cancer cells and releasing cytokines (e.g., IFN-γ) to aid this response. However, during cancer and chronic viral infections, such as with HIV, this CTL response is progressively impaired due to a process called T cell exhaustion. Previous work has shown that the glycoprotein T cell Ig and mucin domain-containing protein 3 (Tim-3) plays a functional role in establishing T cell exhaustion. Tim-3 is highly upregulated on virus and tumor Ag-specific CD8(+) T cells, and antagonizing Tim-3 helps restore function of CD8(+) T cells. However, very little is known of how Tim-3 signals in CTLs. In this study, we assessed the role of Tim-3 at the immunological synapse as well as its interaction with proximal TCR signaling molecules in primary human CD8(+) T cells. Tim-3 was found within CD8(+) T cell lipid rafts at the immunological synapse. Blocking Tim-3 resulted in a significantly greater number of stable synapses being formed between Tim-3(hi)CD8(+) T cells and target cells, suggesting that Tim-3 plays a functional role in synapse formation. Further, we confirmed that Tim-3 interacts with Lck, but not the phospho-active form of Lck. Finally, Tim-3 colocalizes with receptor phosphatases CD45 and CD148, an interaction that is enhanced in the presence of the Tim-3 ligand, galectin-9. Thus, Tim-3 interacts with multiple signaling molecules at the immunological synapse, and characterizing these interactions could aid in the development of therapeutics to restore Tim-3-mediated immune dysfunction.

Optic Disc Elevation Secondary to Cerebral Malaria Resolves Completely With Mannitol Administration and Corresponds to Clinical Improvement.

This case report describes a 14-year-old boy presenting with cerebral malaria in a resource-limited setting. The patient exhibited optic disc elevation, indicating increased intracranial pressure (ICP). Due to the unavailability of advanced neuroimaging, point-of-care ultrasound (POCUS) was employed to assess the optic disc. After administration of a weight-based dose of mannitol, optic disc elevation resolved completely, accompanied by clinical improvement. This case highlights the potential of POCUS as a valuable tool for the assessment and management of cerebral malaria in resource-limited settings.

Community-Acquired Pseudomonas aeruginosa Meningitis in a Pediatric Patient.

This case report presents a rare and significant case of community-acquired Pseudomonas aeruginosa meningitis in a healthy 13-month-old male patient in rural Liberia. Pseudomonas aeruginosa meningitis, particularly in the absence of predisposing factors, is a rare occurrence with a high mortality rate. The challenges in diagnosing this condition, especially in resource-limited settings, are highlighted. The patient initially presented with fever, seizures, and altered consciousness, and lumbar puncture revealed turbid cerebrospinal fluid (CSF) with elevated white blood cell count. Subsequent CSF culture confirmed Pseudomonas aeruginosa infection. Prompt initiation of appropriate antibiotic therapy, including a push dose of meropenem, resulted in clinical improvement. However, the patient exhibited post-meningitis sequelae, including hearing and visual impairments. Comprehensive follow-up care and rehabilitation services are crucial for managing these long-term complications. By sharing this case, we aim to increase awareness and facilitate early recognition of Pseudomonas aeruginosa meningitis, leading to improved patient care and outcomes in similar clinical scenarios.