The cellular network sustained by endogenous catecholamines in human lymphocytes. Speculative scheme depicting the possible actions of endogenous catecholamines produced and released by human lymphocytes in the development of the immune response. Tregs constitutively express TH, the key enzyme in the synthesis of catecholamines, dopaminergic receptors, and α- and β-ARs, and contain high amounts of catecholamines stored in reserpine-sensitive compartments. Upon release, endogenous catecholamines (likely DA) subserve an autocrine/paracrine modulatory loop involving the activation of dopaminergic D1-like (D1/D5) receptors, leading to impaired suppressive activity of Tregs toward mitogen-induced Teff proliferation. In addition to the chromaffin granule depletant reserpine (used in the present study), candidate agents that may induce the release of catecholamines from lymphocytes include type I IFNs, tetrabenazine, as well as even high [K⁺]_e. The picture also summarizes data from available literature, showing that, in the absence of stimulation, effector T lymphocytes express dopaminergic receptors and α- and β-ARs and contain trace amounts of DA, NE, and E. Upon stimulation, intracellular catecholamines increase by several 10-fold, and expression and function of both dopaminergic receptors and ARs may also undergo significant changes. Under these conditions, endogenous catecholamines either may directly affect cell survival and apoptosis from within the cell (lightning bolts), or they can be released (red arrows) to act upon lymphocytes themselves and/or upon neighboring cells. Dopaminergic receptors and α- and β-ARs on Teffs may also represent the targets for catecholamines released by nearby Tregs, which might also result in direct activation of nearby Teffs, resulting, for example, in cytokine secretion and integrin-mediated T-cell adhesion to the extracellular matrix (and, in turn, activated Teffs themselves may represent local sources of DA acting upon Tregs and finally resulting in down-regulation of their inhibitory function). Question marks highlight various issues that await clarification. For the sake of clarity and simplicity, the picture does not include the potential role of catecholamines that are normally present in the extracellular space or that can be released from sympathoadrenergic terminals innervating lymphoid organs and tissues, nor does it include catecholamines, which lymphocytes can encounter when they enter the brain in physiological (or pathological) situations. Please see “Discussion” for a detailed discussion of the various aspects depicted in the figure as well as for specific bibliographic references.