The Short Isoform of the CEACAM1 Receptor in Intestinal T Cells Regulates Mucosal Immunity and Homeostasis via Tfh Cell Induction

Abstract

Summary Carcinoembryonic antigen cell adhesion molecule like I (CEACAM1) is expressed on activated T cells and signals through either a long (L) cytoplasmic tail containing immune receptor tyrosine based inhibitory motifs, which provide inhibitory function, or a short (S) cytoplasmic tail with an unknown role. Previous studies on peripheral T cells show that CEACAM1-L isoforms predominate with little to no detectable CEACAM1-S isoforms in mouse and human. We show here that this was not the case in tissue resident T cells of intestines and gut associated lymphoid tissues which demonstrated predominant expression of CEACAM1-S isoforms relative to CEACAM1-L isoforms in human and mouse. This tissue resident predominance of CEACAM1-S expression was determined by the intestinal environment where it served a stimulatory function leading to the regulation of T cell subsets associated with generation of secretory IgA immunity, the regulation of mucosal commensalism, and defense of the barrier against enteropathogens.

CEACAM1 regulates TIM-3-mediated tolerance and exhaustion

“…Co-immunoprecipitation of CEACAM1 and TIM-3 was confirmed with activated primary human T cells (Extended Data Fig. 3b) and primary mouse T cells from either Ceacam1–4L Tg Ceacam1 −/− mice 6 or Ceacam1–4S Tg Ceacam1 −/− mice 10 (transgenic mice in which CEACAM1 isoforms containing a long (L) or short (S) cytoplasmic tail, respectively, are conditionally overexpressed in T cells) 7 (Extended Data Fig. 3c).…”

“…Considering that TIM-3, like cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1), is being targeted for cancer immunotherapy, it is important to identify the circumstances under which TIM-3 can inhibit and activate T-cell responses. Here we show that TIM-3 is co-expressed and forms a heterodimer with carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), another well-known molecule expressed on activated T cells and involved in T-cell inhibition 6–10 . Biochemical, biophysical and X-ray crystallography studies show that the membrane-distal immunoglobulin-variable (IgV)-like amino-terminal domain of each is crucial to these interactions.…”

CEACAM1 induces B-cell survival and is essential for protective antiviral antibody production

“…The CEACAM1 ectodomain is composed of four (CEACAM1-4) or two (CEACAM1-2) highly glycosylated Ig-like domains, which are highly flexible and participate in anti-parallel (trans) and parallel (cis) homophilic binding 19 . The isoform with the short cytoplasmic tail (CEACAM1-S) can bind calmodulin, tropomyosin, actin, annexin II and PDIP38, and is phosphorylated on Ser449 through protein kinase C [20][21][22] . The isoform with the long cytoplasmic tail (CEACAM1-L) contains two additional immunoreceptor tyrosine-based inhibitory motif-carrying segments 17,23 .…”

“…Although Ceacam1 À / À mice do not exhibit this broad CEACAM1 expression, they develop normally and, in the absence of specific challenges, show no signs of disease 27 . CEACAM1 has been described primarily as a regulator of T cells in the gut 20,[28][29][30] . Expression of CEACAM1-L inhibits T-cell proliferation and therefore prevents inflammatory bowel disease 30 .…”

“…Expression of CEACAM1-L inhibits T-cell proliferation and therefore prevents inflammatory bowel disease 30 . Expression of CEACAM1-S is essential for the development of follicular T helper cell-driven IgA production by gut B cells 20 . CEACAM1 also acts as a co-stimulatory molecule for T-cell receptor and BCR signalling [31][32][33] .…”