Human Oral Epithelial Cells Impair Bacteria-Mediated Maturation of Dendritic Cells and Render T Cells Unresponsive to Stimulation

Abstract

The oral mucosa is a first line of defense against pathogenic organisms and yet tolerates food antigens and resident bacteria. Mucosal epithelial cells are emerging as important regulators of innate and adaptive immune responses. However, the contribution of oral epithelial cells (OECs) determining oral immunity is understudied. Here, we evaluated the ability of H413 and TR146 cells, two OEC lines derived from human oral squamous cell carcinomas, and primary OECs to modulate immune responses to a cocktail of Gram + and Gram − bacteria known as MV130. OECs expressed CD40 constitutively and class II major histocompatibility complex (MHC II) molecules when stimulated with IFNγ, but not CD80 or CD86. Dendritic cells (DCs) treated with bacteria in co-culture with OECs did not fully mature, as judged by the expression of MHC II, CD80 and CD86, and barely released IL-12 and TNFα, compared to control DCs. Furthermore, in the presence of OECs, DCs were unable to stimulate allogenic naive CD4 T cells to produce IFNγ and TNFα. Similarly, OECs in culture with total CD4 T cells or Th1 cells stimulated with anti-CD3 and anti-CD28 antibodies abrogated CD25 and CD69 expression, T cell proliferation and the release of IFNγ and TNFα. The inhibition on T cell activation by OECs was cell-contact dependent, TGFβ independent and largely irreversible. Overall, this behavior of OECs is likely key to avoid immune system over-reaction against resident bacteria.

Sublingual Bacterial Vaccination Reduces Recurrent Infections in Patients With Autoimmune Diseases Under Immunosuppressant Treatment

“…None of the subjects included in the study had any autoimmunity outbreak following mucosal immunotherapy. We believe the high levels of IL-10 released by innate and adaptive immune cells in vitro and in vivo following MV130 and MV140 may account, at least partially, for this protection (23,27,28).…”

“…The non-specific effect of MV130 and MV140 in clinical studies conferring protection against a broad range of pathogens has led to their inclusion as putative TIbVs (10). The mechanism of action immunomodulating the immune response of both mucosal bacterial preparations has been further studied in vivo and in vitro (23,27,28). In this regard, when MV130 and MV140 are administered sublingually to mice, a potent systemic Th1/Th17 and IL-10 response is observed (23,27).…”

Bacterial Mucosal Immunotherapy with MV130 Prevents Recurrent Wheezing in Children: A Randomized, Double-Blind, Placebo-controlled Clinical Trial

“…We did not directly address a mechanistic evaluation of MV130 on samples from the children included in the DBPC by assessing immunological parameters that might correlate with the clinical outcome ( 39 ). This would have shed further light on the mechanism of protection of MV130 ( 16 , 40 , 41 ). On the other hand, whether immunotherapy with MV130 may impact the airway microbiome would have been very interesting to address, as it may influence susceptibility versus resilience to viral infection ( 42 ).…”

Oral Versus Gastrointestinal Mucosal Immune Niches in Homeostasis and Allostasis

“…Similarly, DCs in co-culture were not able to stimulate allogeneic naive CD4+ to produce INFγ and TNFα, when placed under these conditions or in the presence of Th1, anti-CD3 and anti-CD28 cells. This is thought to be one of the strategies of oral epithelial cells to avoid hyper reaction of the immune system against resident bacteria, through the inherent ability of this epithelial barrier to suppress immune responses ( 96 ). The other strategy is related to DCs allowing T cell clones to acquire memory by persisting long-term periods, tolerating self-antigens, or responding rapidly upon re-exposure to noxious antigens ( 83 ).…”