Impaired pathogen-specific CD4⁺ T cell functionality in patients with CLL

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults and remains an incurable disease. Many patients with CLL are affected by non-malignant complications, including infectious diseases, as witnessed during the past years, with very high COVID-19 mortality rates. Accumulating data indicate that T cells might become exhausted in patients with CLL, which might be a contributing factor to poor control of pathogenic infections. Here we developed flow cytometry protocols to combine activation-induced molecule (AIM) assessment and functional read-outs to understand if bacteria- and virus-specific CD4 +T cell responses are impaired in patients with CLL. PBMCs were collected from indolent CLL patients (n=23) and age and gender-matched blood donors (n=17) to assess CD4 +T cell dysfunction against pathogenic bacteria (S. Pneumonia, H. Influenzae, M. Catarrhalis, K. Pneumoniae) and viruses (CMV, EBV, IAV). We show that the frequency of CD4 +T cell responses against most assessed bacterial species was of lower frequencies in CLL patients compared to matched control groups. Both bacteria- and virus-specific CD4 +T cells experienced, in general, signs of functional exhaustion, including diminished capacity to produce IFN-γ, TNF, IL-2, IL-17, and/or IL-21, during indolent CLL. Functional exhaustion was not coupled to increased expression of inhibitory receptors but instead reduced stem-like phenotypes of CD4 +T cells. These data indicate that untreated CLL is coupled to impaired functional capacity of bacteria and virus-specific CD4 +T cells, which might lead to poor pathogen control. Swedish Cancer Foundation(Cancerfonden)