Heated tobacco and cigarette smoke modulate CD4 + T cell activation and neuroinflammation in a context-dependent manner.

Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system (CNS), driven by CD4⁺ T cell-mediated neuroinflammation and influenced by both genetic and environmental factors. Conventional cigarette (CC) smoking is a well-established environmental risk factor for MS, primarily due to its immunotoxic combustion byproducts. Heated tobacco products (HTPs), marketed as safer alternatives due to the absence of combustion, are increasingly adopted by young adults; however, their effects on immune responses and related diseases remain largely unknown. In this study, we evaluated the effects of HTP exposure on experimental neuroinflammation and CD4⁺ T cell responses. Experimental autoimmune encephalomyelitis (EAE)-induced animals were exposed twice daily for 7 days to HTP, CC, or air via a puff-based system delivering equivalent nicotine doses, either prior to disease onset or during the effector phase (7–13 days post-immunization). Pre-EAE exposure to either HTP or CC aggravated clinical symptoms, neurodegeneration, and increased Th1/Th17 cell infiltration into the CNS. During the effector phase, only HTP exposure exacerbated disease severity, neurodegeneration, and peripheral T-cell expansion through enhanced proliferation. In contrast, CC selectively promoted Th22 differentiation and activation of the aryl hydrocarbon receptor (AhR). Ex vivo studies showed that HTP and CC induced distinct T-cell response profiles. CD4⁺ T cells from healthy donors exhibited reduced activation and proliferation in response to HTP, whereas MS-derived cells displayed increased activation and proliferative capacity. CC exposure enhanced activation in both groups without affecting proliferation. These findings clearly demonstrate that HTP exacerbates neuroinflammation and modulates immune responses in a context-dependent manner, challenging their designation as safer tobacco products, particularly in individuals predisposed to autoimmune disorders.