The Global Programme to Eliminate Lymphatic Filariasis (GPELF), implemented more than 20 years ago, includes mass drug administration (MDA) and vector control programmes. Although it has reduced the prevalence of infection in endemic areas, lymphatic filariasis (LF) remains endemic in several low-middle-income countries, particularly in Africa (Ramaiah and Ottesen, 2014; World Health Organization, 2020; World Health Organisation 2021). Wuchereria bancrofti, the causative agent of LF in Africa, has been shown to modulate the human immune system by promoting Th2 immune responses, alternatively activated macrophages and regulatory T and B cell subsets (Babu et al., 2006; Babu et al., 2009; Metenou et al., 2010; Ritter et al., 2019; Wammes et al., 2012). Due to filarial-driven immune modulation, the majority of infected individuals remain asymptomatic, presenting unique immune-profiles but appears to have a reduced immunity against viral, bacterial or other parasitic infections (Arndts et al., 2012; Chatterjee et al., 2014; George et al., 2014; Kroidl et al., 2016; Kwan et al., 2018). Despite the tightly controlled immune-regulation, individuals with LF can also develop severe symptoms like hydrocele or lymphedema (LE) as well as adenolymphangitis (ADL) attacks (World Health Organization, 2020; World Health Organisation 2021). This often leads to reduced quality of life and increased disability-adjusted life years (DALYs), financial losses, and social separation due to the stigmatization (Gyapong et al., 1996; van 't Noordende et al., 2020; Asiedu et al., 2021). Interestingly, the majority of patients suffering from severe pathology have usually cleared the infection and their profiles are characterized by increased antigen-specific Th1 and Th17 responses and constant immune activation (Babu et al., 2009; Babu and Nutman, 2012; Babu and Nutman, 2014). Recently, we showed that CD4⁺ and CD8⁺ T cells are activated during W. bancrofti infection (Kroidl et al., 2019). It is known that constant immune activation accompanied with persistent antigen loads and inflammation can lead to T cell exhaustion, which is defined as T cell dysfunction accompanied with impaired effector function and expression of distinct inhibitory receptors (Wherry, 2011; Wherry and Kurachi, 2015). Important receptors and markers that are associated with such exhaustion include programmed cell death-1 (PD-1), lymphocyte activation gene 3 (LAG-3), killer cell lectin-like receptor subfamily G member 1 (KLRG-1), cluster of differentiation 39 (CD39) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) (Wherry, 2011; Gupta et al., 2015; Wherry and Kurachi, 2015; Dong et al., 2019). By using advanced flow cytometry to explore the expression of these exhaustion-associated markers on T cells, we recently showed that patients with LE due to LF from Ghana harbour distinct exhaustion patterns of memory and effector CD8⁺ T cell subsets compared to W. bancrofti-infected individuals and healthy endemic controls (Horn et al., 2021). Expanding on these findings, we further investigated the exhaustion patterns on CD4⁺ T cell subsets from W. bancrofti-infected individuals, healthy controls and individuals that suffer from LE and revealed an increased expression of these markers on CD4⁺ T cells from patients presenting clinical pathology.

Wuchereria bancrofti-driven immunomodulation is a key feature of this helminth’s survival and homeostasis of host’s immune responses to maintain an asymptomatic disease state (Hoerauf et al., 2005; Babu et al., 2006; Babu et al., 2009; Adjobimey and Hoerauf, 2010; Babu and Nutman, 2012; Wammes et al., 2012; Rajamanickam and Babu, 2013; Metenou et al., 2010; Ritter et al., 2019). However, severe clinical outcomes such as LE can lead to increased DALYs and social stigmatisation (Gyapong et al., 1996; van 't Noordende et al., 2020; World Health Organization, 2021; World Health Organization, 2020; Asiedu et al., 2021). Several studies already characterized CD4⁺ T cells in LE patients and revealed that frequencies of naive, effector memory and central memory CD4⁺ T cells in patients with filarial disease and chronic infections were not different. However, LE patients are characterized by enhanced Th1 and Th17 immune responses accompanied with decreased Th2 cells and increased pro-inflammatory cytokines, chemokines and growth factors that led in the majority of the LE individuals to a clearance of the infection (Debrah et al., 2006; Satapathy et al., 2006; Babu et al., 2009; Bennuru and Nutman, 2009; Bennuru et al., 2010; Babu and Nutman, 2012; Babu and Nutman, 2014). Since filarial infections are chronic diseases, the immune system is constantly encountering filarial-derived antigens which have been recently shown to systemically activate CD4⁺ and CD8⁺ T cell subsets (Kroidl et al., 2019). Such constant activation can lead to T cell-intrinsic regulation, hypo-responsiveness and exhaustion which is important for immune tolerance and control of immune responses (Schwartz, 2003; Wherry, 2011; Wherry and Kurachi, 2015). This has also been observed during parasitic infections with intestinal helminths (Borkow et al., 2000; Leng et al., 2006), murine schistosomiasis (Taylor et al., 2009), Fasciola hepatica (Aldridge and O’Neil, 2016; Sachdev et al., 2017) and Echinococcus multilocularis (Wang et al., 2017; Zhang et al., 2017). Moreover, T cell hypo-responsiveness has been observed during filarial infections with the murine filaria Litomosoides sigmodontis including a crucial role of PD-1 (Taylor et al., 2005; van der Werf et al., 2013; Campbell et al., 2018; Knipper et al., 2019), which is, as mentioned earlier, an important receptor associated with T cell exhaustion when accompanied by LAG-3, KLRG-1, TIM-3 and CD39 (Wherry, 2011; Gupta et al., 2015; Wherry and Kurachi, 2015; Dong et al., 2019). Recently, we revealed that filarial LE patients harbour distinct exhausted effector and memory CD8⁺ T cells that were characterized by the expression of TIM-3, LAG-3, CD39, PD-1 and KLRG-1 (Horn et al., 2021). Expanding on those data, we show here that CD4⁺ T cell subsets from filarial LE individuals also have increased co-expression of exhausted associated receptors. However, further characterization of the CD4⁺ T cell subsets like central memory, effector memory and naïve T cells needs to be performed in future studies to decipher the mechanisms of exhaustion and T cell-specific cytokine responses in patients with disease sequelae. Indeed, an important limitation of the study was that not enough peripheral whole blood could be obtained from the patient cohorts to isolate sufficient amounts of PMBCs to apply another flow cytometry panel and perform re-stimulation experiments for further discrimination of T cell subsets and their cytokine responses, respectively. Nevertheless, the results that were obtained highlight the fact that T cells from individuals who suffer from lymphedema are exhausted and might then in turn lead to impaired immune responses to concomitant infections. Indeed, studies have shown that lymphedema patients have a higher risk for bacterial infection (Dupuy et al., 1999; Dean et al., 2020). It is also known that filarial LE individuals suffer from secondary infections which can cause acute dermatolymphangioadenitis attacks (ADLA) that drive progression of lymphedema (Schacher and Sahyoun, 1967; Olszewski et al., 1993; Shenoy et al., 1995; Olszewski et al., 1997). In summary, the T cell exhaustion patterns described here might be another factor as to why LE patients have a higher risk for bacterial infections and consequently suffering from ADLA. These findings need to be taken into consideration for prevention and control management of filarial lymphedema, with a particular focus on hygiene control management of the affected limbs.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Ethics Committee of the LMU Munich, Germany (17-858, LEDoxy) and (18-377, RHINO), the Ethics Committee at the University Hospital of Bonn, Germany (359/17, LEDoxy) and (041/18, RHINO), the Committee on Human Research Publication and Ethics at the Kwame Nkrumah University of Science and Technology in Kumasi, Ghana (CHRPE/AP/525/17, LEDoxy, CHRPE/AP/235/18, RHINO), the Ghana Food and Drugs Authority (FDA/CT/181 and FDA/CT/181(1)) and the Ghana Health Services (GHS-ERC-007/07/17). The patients/participants provided their written informed consent to participate in this study.

LB, AYD, MC, IK, and LEL conceived and designed the study. SH, DB-W, AW, IK, LB, AYD, JO-M, and KA organized field studies and acquired samples. SH, DB-W, AW, MR, KA, and LEL processed samples, performed analysis, and interpreted the data. SH, IK and MR drafted the manuscript while LB, AYD, JO-M, AW, MC, and AH critically revised the article and controlled the intellectual content. All authors contributed to the article and approved the submitted version.

This work was supported by the German Research Foundation (DFG) within the German-African Projects in Infectiology(RHINO project) [KR3615/1-1 and HO2009/11-1] to AH and IK. Furthermore, AH and IK are also supported by the German Federal Ministry of Education and Research (BMBF) [01KA1601] and as members of the German Centre of Infectious Disease (DZIF) [TI.03.907]. AH is additionally funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy – EXC2151 – 390873048. Finally, MR is financially supported by the BMBF and the Ministry of Culture and Science of the State of North Rhine-Westphalia (MKW) within the framework of the Excellence Strategy of the Federal and State Governments.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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