Staphylococcal enterotoxins stimulate lymphoma-associated immune dysregulation

Abstract

Key Points Staphylococcal enterotoxins stimulate benign T cells to induce activation of the immunoregulatory Stat3/IL-10 axis in malignant T cells. Colonization with enterotoxin-producing Staphylococcus aureus may promote immune dysregulation in cutaneous T-cell lymphoma.

Staphylococcal enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma

“…[12][13][14][15][16][17] STAT3 provides survival signals through upregulation of proto-oncogenes such as Bcl-2 and survivin, 11,15 IL-2 receptor, 63 and pro-oncogenic microRNAs, 64,65 and through downregulation of tumor-suppressive microRNAs such as miR-22. 66 In addition, STAT3 drives expression of suppressor of cytokines signaling, 19 cytokines of the Th2 (IL-5 and IL-13), 67 Th17 (IL-17, IL-22), 21 regulatory T-cell (IL-10) phenotype, 22 and other factors.…”

“…Likewise, SEA induced a significant increase in IL-17 mRNA expression in malignant T cells, but not in nonmalignant T cells, after coculture in Transwell plates ( Figure 3E). Because IL-2 induces IL-17 expression in malignant T cells 21 and because SEA induces IL-2 expression in nonmalignant T cells, 22 cocultures were performed with and without SEA and IL-2-blocking and control antibodies. As shown in Figure 3F, inhibition of IL-2 almost completely blocked IL-17 production in cocultures, indicating the key role of IL-2 in SEA-mediated cross talk between malignant and nonmalignant T-cell lines.…”

“…36,37 For decades, microbes have been suspected to play a key role in CTCL, both as etiologic agents and as drivers of lifethreatening complications. 22,[38][39][40][41][42] So far, firm evidence for a microbial etiology in CTCL is lacking, 43,44 but clinical data indicate that bacteria may play an important role in progression and mortality in advanced disease. 39,40,45 Whereas Staphylococcus aureus is a common commensal organism in healthy individuals, it is a major source of morbidity in CTCL because it causes persistent skin and life-threatening systemic infections 39,42,46,47 seen in 44% to 76% of patients with advanced CTCL.…”

“…[11][12][13][14][15][16][17] Importantly, STAT3 promotes malignant expression of the proinflammatory cytokine interleukin (IL)-17, including a range of cytokines associated with skin inflammation, immune deregulation, and disease progression. [18][19][20][21][22][23] It is well established that STAT3 is tyrosine phosphorylated in vivo in CTCL skin lesions and in peripheral blood Sézary cells. The level of tyrosine phosphorylation in STAT3 increases in advanced disease.…”

Recent advances in primary cutaneous T-cell lymphoma

“…Staphylococcus aureus is a common infectious agent, frequently found in cutaneous CTCL lesions. Krejsgaard et al [32] could demonstrate that staphylococcal enterotoxin can further drive the immune dysregulation in CTCL patients by inducing a crosstalk between malignant and benign T cells that leads to signal transduction and activation of transcription (STAT3)-mediated production of immune suppressive interleukin-10 by the malignant T cells. STAT3 is constitutively phosphorylated and can further be activated in Sézary syndrome cells by interleukin-21 [33].…”