Rheumatologists have long been focused on developing novel immunotherapeutics to manage such prototypic autoimmune disease as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The ultimate challenge in immune suppressing patients with RA and SLE has derived from the dilemma that both protective and harmful immune responses result from adaptive immune responses, mediated by highly diverse, antigen-specific T cells and B cells endowed with powerful effector functions and the ability for long-lasting memory. As regulatory/suppressor T cells can suppress immunity against any antigen, including self-antigens, they emerge as an ideal therapeutic target. Several distinct subtypes of CD8 + suppressor cells (Ts) have been described that could find application in treating RA or SLE. In a xenograft model of human synovium, CD8 + CD28 − CD56 + T cells effectively suppressed rheumatoid inflammation. Underlying mechanisms involve conditioning of antigen-presenting cells (APC). Adoptively transferred CD8 + T cells characterized by IL-16 secretion have also exhibited disease-inhibitory effects. In mice with polyarthritis, CD8 + Ts suppressed inflammation by IFN-γ-mediated modulation of the tryptophan metabolism in APC. In SLE animal models, CD8 + Ts induced by a synthetic peptide exerted suppressive activity mainly via the TGFβ-Foxp3-PD1 pathway. CD8 + Ts induced by histone peptides were found to downregulate disease activity by secreting TGFβ. In essence, disease-specific approaches may be necessary to identify CD8 + Ts optimally suited to treat immune dysfunctions in different autoimmune syndromes.
CD8 T cells stimulated with a suboptimal dose of anti-CD3 antibodies (100 pg/ml) in the presence of IL-15 retain a naïve phenotype with expression of CD45RA, CD28, CD27 and CCR7 but acquire new functions and differentiate into immunosuppressive T cells. CD8+CCR7+ Tregs express FOXP3 and prevent CD4 T cells from responding to T-cell receptor stimulation and entering the cell cycle. Naïve CD4 T cells are more susceptible to inhibition than memory cells. The suppressive activity of CD8+CCR7+ Tregs is not mediated by IL-10, TGF-β, CTLA-4, CCL4 or adenosine and relies on interference with very early steps of the TCR signaling cascade. Specifically, CD8+CCR7+ Tregs prevent TCR-induced phosphorylation of ZAP70 and dampen the rise of intracellular calcium in CD4 T cells. The inducibility of CD8+CCR7+ Tregs is correlated to the age of the individual with peripheral blood lymphocytes of donors older than 60 years yielding low numbers of FOXP3low CD8 Treg cells. Loss of CD8+CCR7+ Tregs in the elderly host may be of relevance in the aging immune system as immunosenescence is associated with a state of chronic smoldering inflammation.
Current treatments for autoimmune disease are hampered by the non-specificity of immunomodulatory interventions, having to accept broad suppression of immunoresponsiveness with potential serious side effects, such as infection or malignancy. The development of antigen-specific approaches, downregulating pathogenic immune responses while maintaining protective immunity, would be a major step forward. One possible approach involves the targeting of physiologic regulatory mechanisms, such as inhibitory CD8 T cells that are now recognized to fine-tune many aspects of immune responses. CD8 T suppressor (Ts) cells may directly inhibit other T cells or condition antigen-presenting cells in such a way that immune amplification steps are dampened. The great promise of CD8 Ts cells lies in their potential to disrupt host-injurious immune responses in a very targeted fashion. For therapeutic purposes, such CD8 Ts cells could either be generated in vitro and transferred into the host or their numbers and activity could be modulated by treating the patient with established or novel immunomodulators. Emerging evidence supports the existence of several different subsets of CD8 Ts cells. While there is still considerable uncertainty about the precise molecular mechanisms through which CD8 Ts cells can reset immune responses to protect the host, their potential diagnostic and therapeutic use is intriguing and has focused renewed interest.
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