## 3 Results
### Modulation of Lymphocyte Function  
Lymphocytes are white blood cells grouped in B cells, T cells, and natural killer (NK) cells [55]; B cells are involved in humoral immunity and counteract pathogens through the release of antibodies and also promote clearance of cellular debris; T cells are involved in immune memory, host defence, and inflammatory response, thanks to their differentiation in cell subtypes, including memory and effector T cells [55]. Effector T cells are distinguished in CD8+ T cells, characterized by antigen-specific cytotoxicity and TNF-\(\alpha\) and IFN-\(\gamma\) production, and in CD4+ T cells, which are further subdivided into helper T cells, such as the Th1, Th17, and Th2 subsets [55]. The Th1 subset activates macrophages, produces IFN-\(\gamma\), and is responsible for pathogen clearance; moreover, it plays a crucial role in autoimmune diseases and in chronic inflammatory disorders, along with the Th17 subset, which is responsible for the recruitment of neutrophils [56]. By contrast, Th2 cells release anti-inflammatory cytokines, such as IL-4, stimulate B cell proliferation and are involved in allergic response. CD4+ T cells can be also differentiated in T-regulatory cells (Tregs), which have regulatory properties to avoid autoimmunity response [55]. Different studies highlighted a possible modulation by caryophyllene sesquiterpenes of lymphocyte function; in particular, [PERSON] and colleagues [46; 47] showed that both \(\beta\)-caryophylleneand \(\beta\)-caryophyllene oxide were nonmutagenic in human isolated primary lymphocytes, thus suggesting their safe use. Moreover, \(\beta\)-caryophyllene (0.5-100 \(\upmu\)M) resulted in being able to protect lymphocytes from the clastogenic damage of ethyl methane sulfonate, likely acting through desmutagenic mechanisms [46]. [PERSON] et al. [44] studied the ability of \(\beta\)-caryophyllene to modulate the balance of Th1 and Th2 cells in an in vitro model of multiple sclerosis. To this end, spleen lymphocytes isolated from experimental autoimmune encephalomyelitis (EAE) mice, a murine multiple sclerosis model, were exposed to myelin oligodendrocyte glycoprotein (MOG\({}_{35-55}\)) and \(\beta\)-caryophyllene 0.2 and 1 \(\upmu\)M. Treatment with \(\beta\)-caryophyllene affected cell proliferation and decreased the MOG\({}_{35-55}\)-induced expression of the pro-inflammatory cytokines IFN-\(\gamma\) and IL-17 (produced by Th1 and Th17, respectively), while enhancing the release of the anti-inflammatory IL-4 and IL-10 (produced by Th2); as a result, the ratios between IFN-\(\gamma\)/IL-4 and IL-17/IL-10 were decreased [44]. These results suggested that \(\beta\)-caryophyllene can protect against multiple sclerosis by attenuating lymphocyte autoreactivity and limiting the inflammatory response through stimulating the activation of Th2 anti-inflammatory cells. Similarly, a 1 h exposure to \(\beta\)-caryophyllene 1-100 \(\upmu\)M enhanced the IL-10 levels and decreased the release of IFN-\(\gamma\), without affecting IL-4 levels, in MOG\({}_{35-55}\)-treated T-lymphocytes isolated from EAE mice; this effect was found to be associated with the activation of CB2 receptors, as confirmed by the disappeared effects in the presence of the selective AM630 CB2 antagonist [45]. Indeed, the activation of CB2 receptors has been reported to inhibit lymphocyte T migration, to modulate the immune system, and to counteract the inflammatory response [45]. These protective effects seem to be related to the activation of the PI3K/Akt signaling pathway [44], as displayed by [PERSON] et al. for \(\beta\)-caryophyllene [30]. As mentioned above, Th2 cells also play a central role in allergic disease and airway hyperreactivity; indeed, they promote eosinophils recruitment, mast cell growth, mucus hypersecretion, and IgE synthesis through the release of cytokines such as IL-4, IL-5, IL-9, and IL-13 [56]. Therefore, their modulation can be approached as a possible strategy against allergy and asthma.