Trans-Epithelial Immune Cell Transfer during Suckling Modulates Delayed-Type Hypersensitivity in Recipients as a Function of Gender

Newborns and infants present a higher susceptibility to infection than adults, a vulnerability associated with deficiencies in both the innate and adaptive immune systems. Innate immune receptors are sensors involved in the recognition and elimination of microbes that play a pivotal role at the interface between innate and adaptive immunity. Pentraxin 3 (PTX3), the prototypic long pentraxin, is a soluble pattern recognition receptor involved in the initiation of protective responses against selected pathogens. Because neonates are generally resistant to these pathogens, we suspected that PTX3 may be provided by a maternal source during the early life times. We observed that human colostrum contains high levels of PTX3, and that mammary epithelial cell and CD11b+ milk cells constitutively produce PTX3. Interestingly, PTX3 given orally to neonate mice was rapidly distributed in different organs, and PTX3 ingested during lactation was detected in neonates. Finally, we observed that orally administered PTX3 provided protection against Pseudomonas aeruginosa lung infection in neonate mice. Therefore, breastfeeding constitutes, during the early life times, an important source of PTX3, which actively participates in the protection of neonates against infections. In addition, these results suggest that PTX3 might represent a therapeutic tool for treating neonatal infections and support the view that breastfeeding has beneficial effects on the neonates’ health.

Section: Discussionsupporting

confidence: 79%

Prototypic Long Pentraxin PTX3 Is Present in Breast Milk, Spreads in Tissues, and Protects Neonate Mice from Pseudomonas aeruginosa Lung Infection

Jaillon

Mancuso

Hamon

et al. 2013

“…Such maternally inherited T cells, acquired during breastfeeding, protect mice against rejection of semiallogeneic skin grafts (47) and affect delayed-type hypersensitivity (48).…”

Section: Discussionmentioning

confidence: 99%

BTN1A1, the Mammary Gland Butyrophilin, and BTN2A2 Are Both Inhibitors of T Cell Activation

Smith

Knezevic

Ammann

et al. 2010

115

131

Butyrophilin (BTN) genes encode a set of related proteins. Studies in mice have shown that one of these, BTN1A1, is required for milk lipid secretion in lactation, whereas butyrophilin-like 2 is a coinhibitor of T cell activation. To understand these disparate roles of BTNs, we first compared the expression and functions of mouse Btn1a1 and Btn2a2. Btn1a1 transcripts were not restricted to lactating mammary tissue but were also found in virgin mammary tissue and, interestingly, spleen and thymus. In confirmation of this, BTN1A1 protein was detected in thymic epithelial cells. By contrast, Btn2a2 transcripts and protein were broadly expressed. Cell surface BTN2A2 protein, such as the B7 family molecule programmed death ligand 1, was upregulated upon activation of T cells. We next examined the potential of both BTN1A1 and BTN2A2 to interact with T cells. Recombinant Fc fusion proteins of murine BTN2A2 and, surprisingly BTN1A1, bound to activated T cells, suggesting the presence of one or more receptors on these cells. Immobilized BTN-Fc fusion proteins, but not MOG-Fc protein, inhibited the proliferation of CD4 and CD8 T cells activated by anti-CD3. BTN1A1 and BTN2A2 also inhibited T cell metabolism, IL-2, and IFN-γ secretion. Inhibition of proliferation was not abrogated by exogenous IL-2 but could be overcome following costimulation with high levels of anti-CD28 Ab. These data are consistent with a coinhibitory role for mouse BTNs, including BTN1A1, the BTN expressed in the lactating mammary gland and on milk lipid droplets.

“…Others have demonstrated dam to pup transfer of milk immune cells and suggested that they conferred short-term, passive, cellular immunity (7–10). However, previous work from this laboratory, showing persistence of lactationally-transferred immunity to adulthood (11), suggested the existence of a more active mechanism through which transferred cells instructed development of the neonate’s T cell repertoire. Here we provide evidence in support of such a mechanism.…”

Section: Introductionmentioning

confidence: 88%

Maternal Milk T Cells Drive Development of Transgenerational Th1 Immunity in Offspring Thymus

Ghosh

Nguyen

Muller

et al. 2016

Self Cite

Using multiple murine foster-nursing protocols, thereby eliminating placental transfer and allowing a distinction between dam- and pup-derived cells, we show that foster nursing by an immunized dam results in development of CD8+ T cells in non-immunized foster pups that are specific for antigens against which the foster dam was immunized (Mycobacterium tuberculosis or Candida albicans). We have dubbed this process “maternal educational immunity” to distinguish it from passive cellular immunity. Of the variety of maternal immune cells present in milk, only T cells were detected in pup tissues. Maternal T cells, a substantial percentage of which were CD4+MHCII+, accumulated in the pup thymus and spleen during the nursing period. Further analysis of maternal cells in the pup thymus showed a proportion was positive for maternal immunogen-specific MHCII tetramers. To determine the outcome of antigen presentation in the thymus, the maternal or foster pup origin of immunogen-responding CD8+ cells in foster pup spleens was assessed. While about 10% were maternally-derived in the first few weeks after weaning, all immunogen-responding CD8+ T cells were pup-derived by 12 weeks of age. Pup-derived immunogen-responsive CD8+ cells persisted until at least 1 year of age. Passive cellular immunity is well accepted and has been demonstrated in the human population. Here we show an arguably more important role for transferred immune cells: the direction of offspring T cell development. Harnessing maternal educational immunity through pre-pregnancy immunization programs has potential for improvement of infant immunity.