Filarial Lymphedema Patients Are Characterized by Exhausted CD4+ T Cells

Abstract

Worldwide, more than 200 million people are infected with filariae which can cause severe symptoms leading to reduced quality of life and contribute to disability-adjusted life years (DALYs). In particular, lymphatic filariasis (LF) caused by Wuchereria bancrofti can lead to lymphedema (LE) and consequently presents a serious health problem. To understand why only a fraction of the infected individuals develop pathology, it is essential to understand how filariae regulate host immunity. The central role of T cells for immunity against filariae has been shown in several studies. However, there is little knowledge about T cell exhaustion, which causes T cell dysfunction and impaired immune responses, in this group of individuals. Recently, we showed that LE patients from Ghana harbor distinct patterns of exhausted effector and memory CD8+ T cell subsets. Based on these findings, we now characterized CD4+ T cell subsets from the same Ghanaian patient cohort by analyzing distinct markers within a 13-colour flow cytometry panel. We revealed that LE patients had increased frequencies of CD4+ T cells expressing exhaustion-associated receptors such as KLRG-1, TIM-3 and PD-1 compared to healthy endemic normal and W. bancrofti-infected individuals. Moreover, CD4+ T cells in LE patients were characterized by distinct co-expression patterns of inhibitory receptors. Collectively with the previous findings on CD8+ T cell exhaustion patterns, the data shown here demonstrates that filarial LE patients harbor distinct subsets of exhausted T cells. Thus, T cell exhaustion patterns in LE patients need attention especially in regards to susceptibility of concomitant infections and should be taken into consideration for LE management measures.

Stage-Dependent Increase of Systemic Immune Activation and CCR5+CD4+ T Cells in Filarial Driven Lymphedema in Ghana and Tanzania

“…In this study, a small subset of filarial LE participants from Ghana ( n = 25) was initially sampled and compared with uninfected control ( n = 34) and Wb-infected ( n = 10) individuals. This same participant cohort was recently seen to display distinct patterns of exhausted effector and memory CD4 + and CD8 + T cell subsets and, thus, we were interested in determining if they also displayed altered activation profiles, since T cell exhaustion is often caused by immune activation, persistent antigen stimulation, and inflammation [ 17 , 18 , 25 , 26 ]. Building on our previous analysis, we conducted a more in-depth evaluation of immune activation patterns in filarial lymphedema participants with different stages by including more participants from two different study sites; we showed that there is indeed an increase in systemic CD4 + T cell activation associated with the progression of chronic LE within a relatively large cohort of LE participants.…”

“…CCR5 is a chemokine that has classically been known as a common co-receptor for HIV on CD4 + T cells, but it also plays a role in other bacterial, viral, and parasitic infections [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. While there have been few studies examining the profile of CCR5 and other chemokines in relation to filarial LE, our group previously examined the frequencies of CCR5 and an array of memory markers among a Ghanaian cohort of individuals that suffer from LE in comparison to other non-LE individuals residing in filarial endemic areas [ 17 , 18 ]. We saw evidence of higher frequencies of CD8 + CCR5 + per se, as well as increased frequencies of CCR5 + CD45RA − memory T cells among the LE group.…”

“…Another marker which was seen to be altered during chronic LE is programmed cell death protein 1 (PD-1); during inflammation, PD-1 plays an immunoregulatory role, acts as an immune barrier molecule to down-regulate T cell activities, and helps to control the T cell response and maintain peripheral tolerance [ 17 , 18 , 36 , 37 ]. To better characterize important markers related to T cell exhaustion in LE, our group previously defined the co-expression of PD-1, IFN-γ, and IL-10 on exhausted memory and effector populations in a subset of Ghanaian LE individuals [ 17 , 18 ]. We chose, in the current study, to focus primarily on PD-1 to characterize exhausted T cells in a larger cohort of LE individuals.…”

“…Our own previous studies have shown systemic activation on CD4 + T cells with increased expression of CD4 + HLA-DR + CD38 + T cells in individuals infected with W. bancrofti in a cohort in Southwest Tanzania; however, those previous studies did not focus on individuals with chronic LE; therefore, the small numbers of individuals included were not differentiated from those with ongoing helminth infections [ 16 ]. Moreover, our group has previously found an altered expression of exhausted CD8 + and CD4 + T cells within a filarial LE cohort compared to asymptomatic W. bancrofti -infected individuals, as seen by the change in expression of receptors, including programmed cell death-1 (PD-1), killer cell lectin-receptor subfamily G member 1 (KLRG-1), lymphocyte activation gene 3 (LAG-3), and T-cell immunoglobulin and mucin-domain containing-3 (Tim-3) [ 17 , 18 ]. These previous studies only included limited numbers of lymphedema participants, making it difficult to evaluate any immunological differences between the LE stages.…”

Reduced Type 2 Innate Lymphocyte Cell Frequencies in Patent Wuchereria bancrofti-Infected Individuals

“…In detail, the immunological characterizations of W. bancrofti -infected, LE and EN individuals show that W. bancrofti (e.g., CFA+MF+ individuals) induce increased levels of regulatory T (Treg) and B cells (Breg) in the peripheral blood accompanied by regulatory and type 2 immune responses including IL-10, IL-4, IL-5, TGF-β and IgG4 [ 5 , 8 , 9 , 10 , 11 , 12 ]. In contrast, LE individuals are associated with enhanced Th1, Th17 and pro-inflammatory responses [ 12 , 13 , 14 , 15 , 16 ], and harbor exhausted T cell populations in peripheral blood [ 17 , 18 ]. However, reports about the immunological characterization of individuals who cleared the infection (PI; previously infected individuals) due to MDA are sparse.…”