Adaptive Cell-Mediated Immunity in the Mammary Gland of Dairy Ruminants

Abstract

Mastitis is one of the greatest issues for the global dairy industry and controlling these infections by vaccination is a long-sought ambition that has remained unfulfilled so far. In fact, gaps in knowledge of cell-mediated immunity in the mammary gland (MG) have hampered progress in the rational design of immunization strategies targeting this organ, as current mastitis vaccines are unable to elicit a strong protective immunity. The objectives of this article are, from a comprehensive and critical review of available literature, to identify what characterizes adaptive immunity in the MG of ruminants, and to derive from this analysis research directions for the design of an optimal vaccination strategy. A peculiarity of the MG of ruminants is that it does not belong to the common mucosal immune system that links the gut immune system to the MG of rodents, swine or humans. Indeed, the MG of ruminants is not seeded by lymphocytes educated in mucosal epithelia of the digestive or respiratory tracts, because the mammary tissue does not express the vascular addressins and chemokines that would allow the homing of memory T cells. However, it is possible to elicit an adaptive immune response in the MG of ruminants by local immunization because the mammary tissue is provided with antigen-presenting cells and is linked to systemic mechanisms. The optimal immune response is obtained by luminal exposure to antigens in a non-lactating MG. The mammary gland can be sensitized to antigens so that a local recall elicits neutrophilic inflammation and enhanced defenses locally, resulting from the activation of resident memory lymphocytes producing IFN-γ and/or IL-17 in the mammary tissue. The rational exploitation of this immunity by vaccination will need a better understanding of MG cell-mediated immunity. The phenotypic and functional characterization of mammary antigen-presenting cells and memory T cells are amongst research priorities. Based on current knowledge, rekindling research on the immune cells that populate the healthy, infected, or immunized MG appears to be a most promising approach to designing efficacious mastitis vaccines.

Immune defenses of the mammary gland epithelium of dairy ruminants

“…Although there is no organised lymphoid formation in the healthy MG, except in the Furstenberg's rosette of infected glands, a few lymphocytes are scattered within the epithelium and in the connective sub-epithelial tissue (6,182,183). In the lactating mouse MG, only 2% of leucocytes (CD45 pos ) are B lymphocytes and 10% T lymphocytes (10).…”

“…Lymphocytes can be seen between epithelial cells, sometimes associated with damaged epithelial cells or even within swelled cells, suggesting that they actually had caused the damage (147). A few publications report the influx of lymphocytes into milk shortly after the onset of inflammation (183). Activated T lymphocytes are constantly excreted in milk from healthy glands (184), and T lymphocytes constitute a sizeable proportion of milk leucocytes of MGs infected with streptococci or staphylococci (185,186).…”

“…This inflammatory response is associated with the local production of IL-17A and IFN-g and depends on the induction of CD4+ Th17 cells by immunisation (202,203). This mammary antigen-specific response (mASR) supposes that at steady state (without inflammation or epithelial leakiness to explain the paracellular passage of ovalbumin, a 40 kDa protein of 4 nm in diameter) the mammary epithelium is able to sample the lumen, take up an antigen, process it, and present it to resident memory lymphocytes that in turn trigger an inflammatory response on the part of the epithelium (183). The mASR can synergise with the innate immune response to MAMPs (77), so that it can be put forward that this type of immunity could amplify the response to infection and be a vaccine target (204).…”

“…In response to these cytokines, both epithelial self-defence (antimicrobial peptides and enzymes) and leukocyte help (recruitment by chemokines) are enhanced. Moreover, vaccination could seed the mammary epithelium and subepithelial stroma with resident memory lymphocytes, with the potential of a quicker and more effective immune response than before immunization (183). It is therefore tempting to view vaccination as a tool to reprogram the response of the mammary epithelium to infection by mastitis-associated bacteria.…”

Emerging roles of noncoding micro RNAs and circular RNAs in bovine mastitis: Regulation, breeding, diagnosis, and therapy

“…Traditional mastitis vaccine has been shown to have high rates of immunization failure or insufficient immune response. Various reasons may contribute to the failure of traditional vaccine, such as poor immunogenicity of the antigen ( Rainard et al, 2022b ), the lack of a suitable drug delivery system ( Wang K. et al, 2022 ), the effect of immune inductive sites ( Rainard et al, 2022a ), and errors due to manual operation. In recent years, differing from previous vaccine strategies that were based on biological carriers such as engineered bacteria or adenovirus ( Lasaro and Ertl, 2009 ), or specific antigens combined with immune adjuvants ( Liu et al, 2021 ; Campra et al, 2022 ), a new vaccine development platform based on nucleic acid [DNA ( Vogel and Sarver, 1995 ) or RNA ( Geall et al, 2013 )] has emerged.…”