With this purpose, we first introduce the basic immunological theory suggested by this model. under control of Tregs if the responding clone has a high autoimmune potential. Such infections promote persistent inflammation and possibly fatigue. We then hypothesized that ME/CFS is a condition characterized by a predominance of this type of infections under control of Tregs. In contrast, healthy individuals are hypothesized to trigger immune responses of a virus-specific clone with a low autoimmune potential. According to this hypothesis, simple model simulations of the CD4+ T-cell repertoire could reproduce the increased density and percentages of Tregs observed in patients suffering from the disease, when compared to healthy controls. A deeper analysis of Tregs in the pathogenesis of ME/CFS will help to assess the validity of this hypothesis. Cloxacillin sodium gene in CD4+ T cells after thymic T-cell development is the hallmark of the natural Tregs (9). In turn, a subset of CD4+ T cells can express the gene in the periphery upon antigen stimulation. These cells are called induced or adaptable Tregs (9). Both types of Tregs are thought to recognize tissue antigens mainly, which ensures the regulation of potentially damaging responses against the body. This hypothesis comes from the observation that the deletion of Tregs or the suppression of their regulatory activity leads to severe and generalized autoimmune responses in inbred mice and humans (10C12). In addition, a reduction of these cells in the periphery is in the origin of naturally occurring type I diabetes in the NOD mouse strain (13). Until now, the role of Tregs on the pathogenesis of ME/CFS has been simply assessed by comparing the respective cell counts between patients and healthy controls. With the exception of a single study (14), the percentage of Tregs tends to be increased in patients when compared to healthy controls (15C17). Similar tendency was found for the transforming growth factor beta (TGF), the Treg-associated suppression cytokine (18, 19). These clinical observations were considered a paradox under the postulated autoimmune origin for ME/CFS (5). However, they prompted us MPL to consider an alternative hypothesis for the pathogenesis of ME/CFS according to which Tregs are elevated resulting from chronic infections that are cross-reactive with self-antigens. The present paper aims then to present different T-cell and viral dynamics consistent with this hypothesis using the cross-regulation model for the immune-physiology of Tregs (20C22). With this purpose, we first introduce the basic immunological theory suggested by this model. We then extend this theory for the role of Tregs in the presence of HHV6, EBV, and HSV1 infections, which helps to discuss their impact on Tregs and on the pathogenesis of ME/CFS. The Cross-Regulation Model for CD4+ T-Cell Dynamics and Its Extension for Chronic Viral Infections The cross-regulation model describes the dynamics of Tregs and effector T cells (Teffs) and their mutual interaction dependent on multicellular conjugates with cognate antigen-presenting cells (cAPCs) (Figure 1) (20, 23). Cloxacillin sodium Conjugation and deconjugation with cAPC are assumed to be the basic cellular process by which Tregs and Teffs become activated and then proliferate; otherwise, they would die by apoptosis with a given rate (Figure 1A). The model assumes that Cloxacillin sodium Teffs can only proliferate following productive conjugations with their cAPCs in absence of Treg co-conjugation (Figure 1B). In contrast, Tregs can only proliferate when co-conjugated with Teffs on the same cAPC (Figure 1C). In that case, Treg proliferation occurs upon receiving growth signals or factors provided by Teffs. At the same time, Tregs are assumed to send a molecular signal (e.g., via TGF) that inhibits the proliferation of Teffs (Figure 1D). It is worth noting that this mechanism is mathematically equivalent to a related one where some Teffs are induced to become Tregs (Figure 1E). If these two mechanisms.