T-cell immunodeficiencies caused by infectious diseases

ACHAIKI IATRIKI | 2024; 43(4):187–194

Review

Despina Papageorgiou, Karolina Akinosoglou


Department of Internal Medicine, University of Patras, 26504, Rio, Patras, Greece

Received: 26 Mar 2024; Accepted: 12 Apr 2024

Corresponding author: Karolina Akinosoglou MD, PhD, Internist-Infectiologist, Associate Professor, Department of Internal Medicine, University of Patras, 26504, Rio, Patras, Greece, E-mail: akin@upatras.gr

Key words: T-cell immunodeficiency, HIV, COVID-19, measles, malaria, leishmaniasis, tuberculosis

 


Abstract

Certain infectious diseases may lead to the development of secondary T-cell immunodeficiency which is described as a transient or persistent impairment of T-cell function and/ or a decrease of T-cell numbers. HIV infection stands as a quintessential example demonstrating the impact of an infectious disease on T-cell function, leading to the development of acquired immunodeficiency syndrome (AIDS). Viral infections, including measles, have been associated with a transient period of immunosuppression, while COVID-19 induces a profound dysregulation of T-cell responses. Parasitic infections, such as malaria and leishmaniasis manipulate the host’s immune system and impair T-cell function by inducing T-cell anergy and exhaustion. Bacterial infections, such as tuberculosis may also lead to the disruption of cellular immune responses. This article examines the range of mechanisms employed by infectious diseases, which contribute to the occurrence of T-cell immunodeficiency.

INTRODUCTION

T-cell immunodeficiency can emerge either as a primary disorder or as a secondary condition resulting from various underlying causes. Primary immunodeficiency syndromes are a heterogenous group of inborn errors of immunity that typically arise from single gene disorders or other maturational abnormalities [1]. In contrast, common causes of secondary immunodeficiencies include infection, medications, malignancy, malnutrition, age extremes and other environmental factors [2]. Secondary immunodeficiency might be defined as a transient or persistent acquired decline of immune cell counts and /or function [3].

T lymphocytes originate from bone marrow progenitors, which then migrate to thymus for maturation, selection and subsequent release into the peripheral circulation. Two major T-cell subsets are defined by the additional expression of either CD4 or CD8 molecules on the cell surface [4]. CD8+ cytotoxic T cells are primarily involved in the destruction of cells infected by foreign agents, such as viruses, and tumor cells expressing appropriate antigens. CD4+ T cells are important for establishing and maximizing the immune response. Through differentiation into T helper cell subsets, they regulate the type of immune response that develops and directs various immune cells, including B cells, macrophages and CD8+ T cells in executing their designated functions [5]. However, some pathogens have evolved mechanisms to interfere with these effector immune responses, manipulate or exhaust the host’s immune system, thereby inducing secondary immunodeficiency [6].

Secondary T-cell immunodeficiency is the primary characteristic of HIV infection [1]. Also, viral infections, including measles, have been associated with transient periods of immunosuppression [7]. Moreover, in several chronic infections persistent antigen stimulation induces decreased T cell effector functions, a condition known as T-cell exhaustion [8]. Various studies suggest that this phenomenon can be extended to protozoan diseases as well [9]. Another strategy employed by parasitic infections to downregulate T-cell function is the induction of T-cell anergy [10]. The objective of this review is to discuss the diverse immunologic mechanisms employed by infectious diseases leading to the emergence of T cell immunodeficiencies (Table 1).

HIV / AIDS

HIV infection has been a global public health issue for over 4 decades and has been associated with more than 40 million deaths [11]. HIV is a single-stranded, enveloped RNA retrovirus from the genus Lentivirus within the family of Retroviridae and is classified into two types, HIV-1 and HIV-2, both of which cause disease in humans. The HIV genome consists of 3 structural genes (gag, pol and env) and six regulatory genes (tat, rev, nef, vif, vpr, and vpu) [12]. HIV infection causes a progressive, multifactorial impairment of the immune system eventually leading to the acquired immunodeficiency syndrome (AIDS) [13]. Systemic chronic immune activation and CD4+ T cell depletion are the hallmarks that characterize the progression of the infection towards immunodeficiency [14].

The infection begins with Env protein, composed of gp120 and gp41 subunits, binding to CD4 molecule and chemokine receptors CCR5 or CXCR4 on target cells [15]. During acute infection CD4+ T cells are severely depleted, especially in gut-associated lymphoid tissue (GALT) which harbors the majority of T lymphocytes in the body [16,17]. There are several mechanisms by which HIV leads infected cells into cell death. HIV induces syncytia formation by the fusion of infected cells expressing Env with the uninfected target expressing a suitable coreceptor (CD4 or CCR5). Syncytia have a short life span and are condemned to die by apoptosis due to genomic instability [18]. In addition, other direct cytopathic effects of HIV on infected cells compromise cell viability. Specific HIV proteins can trigger extrinsic and intrinsic apoptosis pathways. Tat (Trans Activating Factor) is a regulatory HIV protein that has been shown to upregulate CD95 and FasL levels thus enhancing susceptibility to Fas-mediated killing [19]. HIV protease can inactivate anti-apoptotic Bcl-2, while simultaneously activating pro-apoptotic procaspase 8 leading cells to mitochondrial-dependent pathway of apoptosis [20,21]. Furthermore, HIV induces cell death in uninfected cells either by HIV proteins released from infected cells acting on neighboring uninfected cells or by activation-induced cell death [22].

HIV infection also induces chronic immune activation. Viral gene products (Nef, Tat, Vpr, Vpu) and inflammatory cytokines contribute to immune activation by stimulating various immune cells such as monocytes, macrophages and dendritic cells. This hyperimmune activation is characterized by an increased T-cell turnover, non-specific T-cell activation and proliferation, polyclonal activation of B cells and elevated proinflammatory cytokines [23]. Although this leads to increased cell counts, the activated CD4+ T cells have a short life span and are rapidly depleted due to activation-induced cell death or apoptosis. Also, the massive production of proinflammatory cytokines leads to clonal deletion and gradual loss of peripheral CD4+ T cells over time [23].

Without treatment CD4+ T cell counts and immune responses progressively decrease rendering the host susceptible to infections with opportunistic pathogens. Peripheral CD4+ T cell counts below 200 cells/mL mark the onset of acquired immunodeficiency syndrome (AIDS) and patients can present with any number of infections that define AIDS, such as Pneumocystis jirovecii pneumonia, histoplasmosis, toxoplasmosis and coccidioidomycosis [7].

CORONAVIRUS DISEASE 2019

Coronavirus disease (COVID-19) is a disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which emerged as a pandemic since it was first reported in late 2019. Clinical manifestations of the infection range from asymptomatic forms to severe forms with life-threatening pathologies such as acute respiratory distress syndrome (ARDS) [24]. It is now well established that SARS-CoV-2 infection can profoundly affect the functionality of the immune system, leading to dysregulation and immune cell exhaustion [25]. Similar to other viral infections, T cell-mediated immunity plays a vital role in recognizing and controlling SARS-CoV-2 infection. However, T cell dysregulation has been associated with the development of severe disease as well [26,27].

SARS-CoV-2 is able to restrict antigen presentation through downregulation of major histocompatibility complex (MHC) class I and II molecules and consequently lead to the inhibition of T cell-mediated immune responses [28,29]. Also, there is evidence that the virus can suppress and delay the production of type I IFN by expressing factors such as ORF6 and non-structural proteins (nsp) 1 and nsp6 [30,31]. As IFNs promote the survival and effector functions of T cells, impaired T-cell responses can result from deficient IFN production. However, further research is warranted to confirm this possibility [32].

Severe COVID-19 is associated with impaired T-cell responses that manifest as lymphopenia and functional exhaustion of CD4+ and CD8+ T cells. SARS-CoV-2 infection predominantly impacts T lymphocytes, especially CD4+ and CD8+ T cells, leading to a reduction in absolute counts, particularly evident in severely ill patients [33,34]. Studies demonstrated a negative correlation between the viral RNA and CD4+ and CD8+ T cells, suggesting that lymphopenia influenced by SARS-CoV-2 RNA, was closely related to disease severity [35]. Detectable serum SARS-CoV-2 RNA was associated with elevated IL-6 concentration as well [36]. Also, increased concentrations of cytokines, including IL-2R, IL-6, TNF-α and IL-10, were detected in the majority of severe cases, suggesting that cytokine storms might be associated with disease severity [33]. Hence, several mechanisms may act together and overlap in some cases to cause lymphopenia. Direct effects of SARS-CoV-2 on T cells can induce apoptosis. Additionally, lymphopenia may be driven by inflammatory responses like cytokine storm-induced apoptosis and tissue redistribution of lymphocytes [37]. Moreover, T-cell exhaustion may contribute to the observed lymphopenia [34].

T-cell exhaustion is a gradual process of cell function loss, at first detected as a reduced production of IL-2 and proliferative response of CD8+ T cells, followed by loss of ability to produce TNF-α and diminished cytotoxic effect. Later on, complete loss of ability to produce IFN-γ and some chemokines is observed. Eventually this process leads to the loss of effector function, depleted proliferative capacity, suppression of cytotoxic T-cell response and cell death. Along with CD8+ T cells the CD4+ T cells also undergo loss of effector function [38]. Exhausted T cells are characterized by an increased and persistent expression of inhibitory receptors and an altered transcriptional profile [8]. Studies on COVID-19 patients demonstrated an increased expression of inhibitory receptors, including immunoglobulin mucin-3 (TIM-3) and programmed cell death protein-1 (PD-1) on T cells that are associated with functional exhaustion of CD8+ T cells [39]. Also CD8+ T cells which had upregulated NKG2A protein, exhibited an exhausted phenotype [40]. Further research indicated that CD4+ and CD8+ T cells are exhausted in patients who have reduced expression of IFN-γ and IL-21 [39].

Measles

Measles is a highly contagious, potentially fatal but vaccine-preventable disease caused by measles virus. The infection begins in the respiratory tract and systemically spreads to infect multiple organs. Clinical presentation varies, ranging from mild symptoms such as fever, rash and conjunctivitis, to more severe manifestations like pneumonia and encephalitis [41]. In addition, measles was the first infectious disease recognized to increase susceptibility to other infections. A transient period of immunosuppression associated with the infection was initially documented in 1908, when a decrease in tuberculin skin reactivity in measles patients was observed [42]. Although the exact mechanisms remain unclear, lymphopenia, inhibition of lymphocyte proliferation and immune amnesia contribute to the development of immunosuppression.

During measles infection, lymphopenia occurs at the onset of the rash in the majority of measles cases with a decrease in cell numbers of CD4+ T cells, CD8+ T cells, B cells and other cell types. The expression of apoptosis-associated molecules, such as CD95 (Fas) and TNF-related apoptosis-inducing ligand-receptor (TRAIL-R), was upregulated on the cell surface of surviving lymphocytes suggesting that lymphopenia was related to apoptosis [43]. Other types of cell death as well as alterations in lymphocyte trafficking may contribute to lymphopenia [44]. However, as the rash resolves, lymphocyte counts return to normal. In addition, measles virus induces suppression of T-cell proliferation through direct inhibitory signaling to T cells by the viral glycoprotein complex of hemagglutinin (H) and fusion (F) in the membrane of virions or infected cells [45,46]. This inhibitory signal prevents the entry of T cells in the S phase leading to cell cycle retardation and accumulation of cells in G0/G1 phase [47]. Lastly, measles infection induces immune amnesia by infecting and eliminating pre-existing memory T cells as well as B cells that express high levels of CD150. As a result, memory cell repertoires are depleted of many specificities leading to increased susceptibility to infections that are unrelated to measles [48].

Leishmaniasis

Leishmaniasis is a vector-borne tropical disease caused by a diverse group of protozoans of the genus Leishmania. Leishmaniasis is transmitted by female phlebotomine sandflies causing a wide range of clinical syndromes. There are three main clinical manifestations in humans. Cutaneous leishmaniasis (CL) is the least severe form of the disease and is caused by several species such as Leishmania major, Leishmania tropica, Leishmania mexicana and Leishmania amazonensis. Mucocutaneous leishmaniasis (MCL) is caused by L. braziliensis. Visceral leishmaniasis (VL) is the most severe form of the disease that results from the infection with Leishmania donovani and Leishmania infantum strains [49].

Infection with L. amazonensis has been associated with the induction of T-cell anergy to both related and unrelated antigens [50]. T-cell anergy is described as a state of non-responsiveness at the time of T cell stimulation through T cell receptor either due to the absence of costimulatory signals or the expression of immunomodulatory molecules by antigen presenting cells (APCs) [10]. A proposed mechanism for the induction of T cell anergy involves the production of TGF-β by macrophages [50]. Also, in chronic infection persistent antigen presentation promotes T cell exhaustion. During L. mexicana infection dendritic cells (DCs) produce high amounts of TNF which compromises the proliferation and functionality of T cells [51]. Additionally, chronic VL leads to T cell exhaustion through the upregulation of several inhibitory receptors such as PD-1 and CTLA-4 [52,53]. The expression of endogenous mediators, including hypoxia inducible factor 1-α (HIF-1α) and adenosine may also contribute to T cell exhaustion [54]. Lastly, several studies demonstrate that T cell apoptosis which occurs during leishmaniasis, may impact the mechanisms of T cell memory formation and compromise immunity during chronic infection [10].

Malaria

Malaria is an endemic vector-borne parasitic disease caused by protozoan parasites of the genus Plasmodium in tropical and subtropical regions worldwide. Among over 200 species of Plasmodium, Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale and Plasmodium knowlesi are known to cause disease in humans [55]. Malaria is associated with public-health problems resulting from impairment of immune responses [56]. There is evidence that malaria can induce immunosuppression in infected individuals, resulting in increased susceptibility to secondary infections such as non-typhoidal Salmonella [57], HBV [58] and herpes zoster virus (HSV) [59].

The suppression of immune function seen in malaria infection could be attributed to a parasite induced dysfunction of the DCs [60]. Interactions between antigen-presenting DCs and T cells are essential for the induction of an immune response. A parasite-induced failure in DCs function affects the generation of T-helper cell responses. These T cells fail to help B cell responses, reducing the production of antibodies that are necessary to control malaria infection [61]. Various studies have shown that DC phenotype is altered during malaria infection resulting in impaired ability to upregulate the MHC molecule HLA-DR and costimulatory molecules CD86 [62–65]. This altered phenotype has a reduced phagocytic capacity which impairs its ability to process antigens and prime T-cell responses. Another study demonstrated that the reduced effector function of CD4+ T cells during malaria is due to an inability to form a stable, long-lasting connection between T cells and DCs [66].

Furthermore, T-cell exhaustion plays a role in the impairment of T-cell function during malaria infection. Prolonged infection results in dysfunctional parasite specific CD4+ T cells that express exhaustion markers. The upregulation of PD-1 and lymphocyte-activation gene-3 (LAG-3) inhibits T-cell function and affects the ability of CD4+ T cells to produce cytokines [67]. Specifically, PD-1 mediates a reduction in the capacity of parasite-specific CD4+ T cells to proliferate and secrete IFN-γ and TNF-α [68]. Also, a study demonstrated that a dual blockade of PD-1 and LAG-3 improves CD4+ follicular T helper cell numbers and provided evidence that supported the involvement of these inhibitory molecules in T-cell exhaustion during malaria infection [69].

Tuberculosis

Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis. Individuals with certain conditions, including HIV or AIDS are predisposed to an increased susceptibility to the disease. Worldwide, TB ranks as the second most deadly infectious disease, following COVID-19 with estimated mortalities of 1.3 million in 2022 [70]. The adaptive immune response mediated by T cells is critical for control of M. tuberculosis infection [71]. However, M. tuberculosis has employed multiple strategies in order to evade the host’s immune response and undermine T-cell function and survival.

M. tuberculosis delays T-cell priming by impairing DC maturation and interfering with efficient antigen presentation with a variety of mechanisms [72]. However, even with the presence of an effective primary immune response in many cases the lack of sterilizing immunity poses a great challenge [73]. Persistent antigen stimulation leads effector T cells to functional exhaustion by upregulating the expression of inhibitory receptors, such as PD-1 and TIM-3 [74,75]. In addition, one of the main features of the immune response to M. tuberculosis is the formation of an organized structure called granuloma [76]. Although granulomas are important in host protection, they also facilitate persistent infection by establishing an immunosuppressive environment in which IL-10 impairs Th 1 cell response and lysis of infected macrophages by CD8+ T cells [73]. Moreover, within the granuloma transforming growth factor-β restricts CD4+ T-cell function and survival [77]. It is also worth noting that severe TB is associated with a decrease in both CD4+ and CD8+ T-cell numbers [78,79]. The underlying mechanism of lymphopenia remains unclear. Despite this, various mechanisms including inhibition of lymphocyte proliferation by macrophages, M. tuberculosis-induced apoptosis of T cells and M. tuberculosis-mediated bone marrow hematopoietic dysfunction may contribute to the occurrence of lymphopenia. Lymphopenia highlights the impairment of immune function and may lead TB patients to general immunosuppression [80].

CONCLUSION

It is well established that viruses, bacteria and parasites have evolved multiple strategies in order to evade and interfere with the host’s immune system. The interaction between the pathogen and the host’s immune system often results in a profound dysregulation of immune responses that favor the pathogen’s survival and have serious consequences for the host. Within the context of a severe primary infectious disease, T-cell defects involve multiple underlying immunological mechanisms, and it can be therefore difficult to demonstrate and quantify the degree of cellular immunodeficiency. Also, distinguishing patients with a secondary T-cell immunodeficiency from patients with an underlying primary T-cell defect is challenging. In clinical settings, maintaining a heightened clinical suspicion regarding secondary T-cell immunodeficiencies is crucial when encountering patients presenting with recurrent infections and abnormal immunologic assessments.

Conflict of interest: None to declare.

Declaration of funding: None to declare.

Author contributions: KA conceived idea; KA, DP performed literature search; DP wrote manuscript; KA critically corrected manuscript; KA oversaw study.

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