Abstract
Although intestinal epithelial cells (IECs) can express major histocompatibility complex class II (MHC II), especially during intestinal inflammation, it remains unclear if antigen presentation by IECs favours pro- or anti-inflammatory CD4+ T cell responses. Using selective gene ablation of MHC II in IECs and IEC organoid cultures, we assessed the impact of MHC II expression by IECs on CD4+ T cell responses and disease outcomes in response to enteric bacterial pathogens. We found that intestinal bacterial infections elicit inflammatory cues that greatly increase expression of MHC II processing and presentation molecules in colonic IECs. Whilst IEC MHC II expression had little impact on disease severity following Citrobacter rodentium or Helicobacter hepaticus infection, using a colonic IEC organoid-CD4+ T cell co-culture system, we demonstrate that IECs can activate antigen-specific CD4+ T cells in an MHC II-dependent manner, modulating both regulatory and effector Th cell subsets. Furthermore, we assessed adoptively transferred H. hepaticus-specific CD4+ T cells during intestinal inflammation in vivo and report that IEC MHC II expression dampens pro-inflammatory effector Th cells. Our findings indicate that IECs can function as non-conventional antigen presenting cells and that IEC MHC II expression fine-tunes local effector CD4+ T cell responses during intestinal inflammation.
Competing Interest Statement
FP received consultancy or research support from GSK, Novartis, Janssen, Genentech and Roche.
Footnotes
Conflict of Interests: FP received consultancy or research support from GSK, Novartis, Janssen, Genentech and Roche.
Abbreviations
- (IECs)
- Intestinal epithelial cells
- (MHC II)
- Major histocompatibility complex class II
- (IBD)
- Inflammatory Bowel Disease
- (GvHD)
- Graft-versus-host disease
- (Tregs)
- Regulatory T cells
- (A/E)
- Attaching-effacing
- (LPLs)
- Lamina propria leucocytes
- (iCM)
- Inflammatory conditioned medium
- (cCM)
- Control conditioned medium
- (RNA-Seq)
- RNA sequencing
- (APC)
- Antigen presenting cell
- (CIITA)
- class II major histocompatibility complex transactivator
- (H. hepaticus)
- Helicobacter hepaticus
- (C. rodentium)
- Citrobacter rodentium
- (HH7-2tg cells)
- H. hepaticus-specific CD4+ T cells
- (TF)
- Transcription factors
- (PD1)
- Programmed cell death protein 1
- (PD-L1)
- Programmed death-ligand 1
- (MFI)
- Median fluorescent intensity
- (CFU)
- Colony-forming units
- (H&E)
- Hematoxylin and eosin