T cell is one of the major cell types in the human immune system and primarily mediates cellular immunity. Additionally, EVs play an important role as immunomodulators in the communication between T cells and other cells.

On the one hand, EVs in the context of disease exacerbate disease pathology by attenuating T-cell responses. Firstly, tumor-derived EVs have been shown to evade immune surveillance by reducing the function or number of T cells ( Table 1 ). For example, in gastric cancer cells, lysine-specific demethylase 1 inhibited T-cell activation and proliferation via exosomal programmed cell death 1 ligand 1, promoting the development of gastric cancer (14). Invasive breast cancer cell-derived EVs transferred transforming growth factor-β type II receptor to CD8+ T cells (15, 16), while chronic myeloid leukemia cell-derived EVs to T cells (17), promoting T cell depletion, resulting in the failure of immunotherapy. Additionally, myeloma cell line MOPC315.BM-derived EVs promoted myeloma cell escape and progression by modulating the lymphoid-like cell phenotype, in which CD4+ T cells exhibited pro-tumorigenic features, increasing the expression of immune checkpoint PD-1 and CTLA-4 while decreasing the expression of CD27, and facilitating the generation of an immunosuppressive environment (18). Interestingly, CD19+ leukemia cells NALM6-derived EVs carrying CD19 antigen could activate CD19 chimeric antigen receptor-T (CAR-T) cells, and transient activation dramatically promoted the release of a variety of inflammatory cytokines, including IL-2, IL-4, interferon (IFN)-γ, IL-10, IL-6, tumor necrosis factor (TNF)-α, IL2RA, IL-13, LTA and TNFSF18. However, sustained activation caused CD19 CAR-T cells to enter a depleted state, with increased inhibitory receptors PD1 and CTLA4, and significantly increased in the markers of exhaustion CD244 and CD160, and weakened their anti-tumor activity (19). Secondly, EVs are also believed to accelerate the progression of autoimmune diseases ( Table 1 ). (1) In terms of the number of T cells, one research has demonstrated that lncRNA HOXA transcript at the distal tip was upregulated in rheumatoid arthritis (RA) synovial fibroblast cell-derived exosomes and promoted the expression of STAT3 by inhibiting the expression of miR-1908-5p, which increased the proportion of T-helper17(Th17) cells and decreased the proportion of Treg cells in the CD4+ T cell population, leading to increased synovial inflammation and cartilage erosion (20). Similarly, Schneider et al. found that in patients with juvenile idiopathic arthritis, the release of CD73-containing EVs from activated CD8+ T cells promoted adenosine production and inhibited T cell proliferation and function, which synergized with the high ATPase activity of the Treg cells and played a key role in terminating the immune response (21). (2) In terms of the function of T cells, Sun et al. reported that exosomes harvested from the sera of mice with experimental autoimmune myocarditis induced immunometabolic dysfunction of CD4+ T cells through cargo miR-142, thus promoted disease progression (22). These findings underscore the critical role of EVs in modulating T cell responses.

On the other hand, T cells are not only the target cells of EVs, but also can secrete EVs into the target cells to alter or impair biological functions of target cells, leading to disease development. First of all, T cell-derived EVs can induce disease onset and progression by impairing the function of epithelial or endothelial cells. The Ca2+ and cAMP pathways are the major signaling systems of the secretory epithelium and control almost all secretory gland functions, and Ca2+ signaling is essential for controlling fluid and enzyme secretion from exocrine glands. It has been indicated that miR-142-3p was highly expressed in salivary glands of Sjögren’s syndrome patients, including inflammation-infiltrated T cells, which secreted exosomes containing miR-142-3p that significantly down-regulated key components of Ca2+ signaling and cAMP production in salivary gland epithelial cells—SERCA2B, RyR2 and AC9—limited cAMP production, altered calcium signaling, reduced protein production in salivary gland cells, ultimately directly impaired epithelial cell function (23). Furthermore, CD4+ T lymphocytes-derived exosomes transported MEK1/2 and ERK1/2, and activated NADPH oxidase in cardiac microvascular endothelial cells, which played a key role in the pathogenesis of angiosclerosis and coronary microcirculatory dysfunction (24). Secondly, T cell-derived EVs could also cause the disorder of the endocrine system. For instance, exosomes released from T cells contained specific microRNAs that triggered chemokine expression and apoptosis in recipient pancreatic β cells, increasing the incidence of diabetes in non-obese diabetic mice (25).

In conclusion, these studies suggested that T cells can play an immunomodulatory role through EVs regardless of whether they are the source or target cells of EVs; however, T cell subtypes are varied. The specific regulatory mechanisms between EVs and T cell subtypes in different disease settings still need more scientific exploration.

B cells stimulated by antigen can differentiate into effector B cells, which subsequently produce antibodies to mediate humoral immunity. In addition, B cells participate in immune regulation via presenting antigens and secreting cytokines.

It has been observed that when the body is in a pathological condition, EVs can release their contents into B cells, which affects the function of B cells. For example, RA is a chronic autoimmune inflammatory disease. B cells are the central component of the immune pathology of RA. Rincón-Arévalo et al. investigated the effect of medium/large EVs (m/lEVs) and m/lEVs-forming immune complexes from RA patients on B cell activation. They found that these EVs reduced the expression of activation markers, diminished calcium mobilization and decreased tyrosine phosphorylation in activated B cells in vitro ( Table 1 ) (26). These findings suggested that EVs may contribute to the dysregulation of B cell function in RA.

In addition, mixed cryoglobulinemia is a systemic vasculitis mediated mainly by the immune complex and is the most common extrahepatic manifestation associated with hepatitis C virus (HCV), characterized by B cell proliferation and autoantibody production, in which HCV-associated exosomes have been shown to induce B cell activating factor upregulation in macrophages through activation of Toll-like receptor 7 and Nuclear factor-κB (NF-κB), accompanied by phosphorylation of the p65 subunit, stimulating B cell activation to produce excessive anti-HCV antibodies and then leading to the development of mixed cryoglobulinemia symptoms (27).

The above studies suggested that there may be a dual role for EVs in B cell activation, which meant that the effect of EVs on B cell immunoregulatory function in specific diseases remains largely unknown.

Neutrophils are the most abundant granulocyte type, and they are the main effect cells of the body against infection by extracellular pathogens and can be recruited from the blood to act at the site of inflammation of infection. In addition, interactions between EVs and neutrophils have been shown to influence immune regulation.

Lung EVs have been shown to contain protein and dsDNA components, both of which played a critical role in the recruitment of neutrophils during the early stages of bacterial infection (28). In another study, pyroptotic bodies (micron-sized EVs) were characterized in the alveolar lavage fluid during the early phases of acute lung injury. This study confirmed that the release of caspase-1-mediated pyroptosis-dependent vesicles from alveolar macrophages in the early stages of lipopolysaccharide-induced acute lung injury in mice. These EVs encapsulated several injury-associated molecular patterns—including TNF-α, IL-6, IL-1β, fibronectin, HMGB1, heat shock proteins, and s100s—promoting the activation of lung epithelial cells through the p38 MAPK signaling pathway, which led to interstitial vascular edema, recruited neutrophils and participated in uncontrolled inflammatory responses (29).

Neutrophil-derived EVs can cause tissue cell dysfunction and inflammatory chemotaxis, thereby contributing to the development of autoimmune diseases. Firstly, in terms of endothelial cell injury, activated neutrophil-derived EVs containing miR-142-3p and miR-451 have been found to target endothelial cells to trigger an inflammatory cascade reactions and induce direct vascular injury in anti-neutrophil cytoplasmic antibody-associated small vessel vasculitis (30). Moreover, the exosomes in microscopic polyangiitis have also been shown to induce endothelial damage (31). Secondly, in terms of inflammatory chemotaxis, a study by Shao et al. revealed that neutrophils from patients with generalized pustular psoriasis secreted more exosomes than those from healthy individuals, which were then rapidly internalized by keratinocytes. This resulted in the increased expression of inflammatory molecules through the activation of NF-κB and MAPK signaling pathways, exacerbating neutrophil migration and the formation of an autoinflammatory cycle in generalized pustular psoriasis (32).

Generally speaking, EVs can indeed promote the recruitment and migration of neutrophils, but to some extent, it can lead to self inflammatory cycle and cause inflammatory cascade reaction. Further research is needed to clarify the exact mechanism of neutrophil immunoregulation of EVs in diseases.

Monocytes originate from the bone marrow, circulate to the whole body through the blood, and differentiate into macrophages, which play an essential role in immune surveillance and response (33). In addition to direct cell-cell communication, monocytes and macrophages also communicate with other cells through EVs for intercellular communication. The communication mediated by these EVs can also impair immune function and contribute to the pathogenesis of various diseases (33, 34).

On the one hand, EVs have been found to modulate the phenotype and function of monocytes or macrophages, which has a significant impact on the immune function of the body (shown in Figure 1 ). First of all, EVs can induce the immune state of the body toward a pro-inflammatory direction, as demonstrated in Table 1 . (1) In the respiratory system, It has been shown that exosomes presented in alveolar lavage fluid from patients with Lumpy disease induced elevation of IL-1β, IL-6, TNF, CCL2 and reactive oxygen species in monocytes, demonstrating the effect of exosomes on nodular inflammation (35). In addition, SARS-CoV-2 Spike transfected cells could activate microglia through exosomal miR-148a to target the Ubiquitin Specific Peptidase 33/Interferon regulatory factor 9 axis, leading to severe neuroinflammation in the central nervous system (36). (2) In the nervous system, in patients with multiple sclerosis, neurons secreted EVs containing interferon stimulated gene 15 protein. Interferon stimulated gene 15 protein directly activated microglia in a CD11b-dependent manner and promoted the production of chemokines, inflammatory factors and iNOS in microglia (37). (3) In the circulatory system, EVs secreted by trophoblast cells in the placenta of patients with preeclampsia can act as key inflammatory signals driving macrophage M1 polarization to a pro-inflammatory phenotype. It has been shown that trophoblast-derived EVs in preeclampsia women significantly up-regulated macrophage M1 gene markers, such as IL-1β, IL-6 and TNF-α, and significantly down-regulated macrophage CD163 expression compared to trophoblast-derived EVs in normal pregnant women. These results suggested that trophoblast-derived EVs in preeclampsia may be a key inflammatory signal driving macrophage polarization toward pro-inflammatory phenotypes (38). (4) In the digestive system, Crohn’s disease-related EVs were transported from intestinal epithelial cells to macrophages, which not only triggered the inflammatory response (39), but also expanded the replication of secondary bacterial infections in host cells (40). (5) In the urinary and endocrine systems, Leucine-rich α-2-glycoprotein 1-rich lipotoxic renal tubular epithelium-derived EVs induced inflammation and injury in diabetic nephropathy by activating macrophages through a TGFβR1-dependent process (41). Additionally, adipocytes delivered miR-34a to neighboring macrophages via exosomes, resulting in a shift to a pro-inflammatory M1 phenotype that exacerbated obesity-associated systemic inflammation and metabolic dysregulation (42).

Secondly, EVs have been shown to play a role in promoting tumor progression through various oncogenic mechanisms ( Table 1 ). (1) Immunosuppression. For instance, the nasopharyngeal carcinoma cell-derived exosomes RNF126 (43), glioma cell-derived EVs miR-3184-3p (44) and miR-10b-5p (45) altered the tumor immune microenvironment and aggravated tumor progression by up-regulating the expression of M2 polarization-associated factors IL-10, TGF-β, CD163, and Arg-1, as well as down-regulated the expression of M1 polarization-associated factor TNF-α. (2) Proliferation. For example, after radiotherapy, glioblastoma cell exosomal circ_0012381 could induce microglia M2 polarization, reduce their phagocytosis and then promote tumor proliferative capacity (46). Pancreatic cancer cell exosomal FGD5-AS1 have been shown to induce M2 polarization of tumor-associated macrophages, resulting in increased proliferation, migration and invasion (47). (3) Angiogenesis. As shown by gastric cancer cell exosomal miR-519a-3p, which mediated angiogenesis by inducing M2 polarization in intrahepatic macrophages, thus promoted liver metastasis (48). (4) Anti-apoptosis. For example, melanoma cell EVs recombinant heat shock protein 90α could enhance the resistance of monocytes to apoptosis (49).

On the other hand, EVs released by monocytes or macrophages can also aggravate the severity of diseases through different mechanisms. Firstly, they can induce tissue cells damage. For example, in the exosomes secreted by macrophages treated with HIV virus protein, miR-23a and miR-27a impaired the tight junction barrier and mitochondrial function of lung epithelial cells respectively, increasing the susceptibility to alveolar infection and injury (50). Macrophage-derived EVs containing high levels of leucine-rich α-2-glycoprotein 1 (51) or tumor necrosis factor-related apoptosis-inducing ligand (41) have been shown to induce renal tubular epithelial cell injury and apoptosis via corresponding transforming growth factor β receptor 1 (51) or death receptor 5 (41) dependent processes. Secondly, EVs can enhance tumor cell resistance. For instance, the tumor-associated macrophage-derived exosomal lncMMPA promoted tumor proliferation by activating the glycolytic pathway in hepatocellular carcinoma cells (52). MiR-222-3p, an M2 macrophage-derived EVs cargo, mediated gemcitabine resistance in pancreatic cancer (53). Thirdly, EVs can also modulate other immune cells. In the animal model of Guillain-Barré syndrome, M1 macrophage-derived exosomes exacerbated the disease by directly regulating the differentiation (increased proportion) and function (increased IFN-γ intensity) of Th1 effector cells (54). Finally, EVs can inhibit precursor cell differentiation. For example, miR-98, an M1 macrophage-derived exosomal cargo, was transferred to MC3T3-E1 cells and exacerbated bone loss in osteoporosis by inhibiting osteogenic differentiation through downregulation of DUSP1 and activation of the JNK signaling pathway (55).

Although a large number of studies have shown that EVs promoted diseases progression by inducing M2 polarization of macrophages, M2 macrophages could be subdivided into four subtypes, so more future researches are needed to clarify the more accurate influence of EVs on M2 macrophage subtypes.