Review Article

Role of Cellular Immunity in Cow’s Milk Allergy: Pathogenesis, Tolerance Induction, and Beyond

Table 1

Roles of cellular immunity in cow’s milk allergy.

TypeCellRole in cow’s milk allergy

Innate cellsTissue mast cellsAct as key effectors during allergy.
Upon Ig-E or Ig-fLC cross-linking with allergen, 3 classes of biologically active product are secreted [15] as follows.
(1) Prestored cytoplasmic granules:
 (a) biogenic amines (e.g., histamine),
 (b) serglycin proteoglycans (e.g., heparin and chondroitin sulphate),
 (c) serine proteases (tryptases, chymases, and carboxypeptidases),
 (d) some cytokines (e.g., TNF- and VEGFA).
(2) Lipid-derived mediators (prostaglandins, leukotriene B4, cysteinyl leukotrienes, and platelet-activating factors).
(3) Newly synthesized factors (cytokines, chemokines, and growth factors).
BasophilsAct as key effectors during allergy.
Similar to mast cells, upon cross-linkage of IgE, 3 types of mediators can be released [13] as follows.
(1) Preformed, immediately released (e.g., histamine).
(2) Newly synthesized, immediately released (phospholipid metabolites including leukotriene C4).
(3) Newly synthesized, slowly released (cytokines including IL-4).
EosinophilsAct as key effectors during allergy.
Upon activation with cytokine (e.g., IL-5), highly basic and cytotoxic granule proteins are secreted [21] as follows.
(1) Major basic protein/MBP and MBP2.
(2) Eosinophilic cationic protein/ECP.
(3) Eosinophilic peroxidase/EPX.
(4) Eosinophil-derived neurotoxin/EDN.
Inflammatory dendritic cells/DCsAct as the initiator of 2-cell response during allergy.
Inflammatory DCs uptake and process allergens, subsequently presenting allergen-derived peptides to naïve CD4+ T cells.
In the presence of IL-4, DCs polarizing naïve CD4+ T become TH2 cells.
Other innate cells
(neutrophils, NK, MAIT, and T cells)
Unknown roles.

Adaptive cellsCD4+ TH2 cellsAct as the driver of allergic inflammation.
Through cell-contact and cytokines (IL-4 and IL-13), TH2 cells promote immunoglobulin class-switch recombination in B cells to drive IgE production.
CD4+ TReg cellsAct as the suppressor of allergic inflammation, via [60] the following.
(1) Suppression of tissue mast cells, basophils, and eosinophils.
(2) Suppression of inflammatory DCs and induction of tolerogenic DCs.
(3) Suppression of allergen-specific TH2 cells.
(4) Early induction of IgG4 and late decrease in IgE.
B cellsAct as the codriver of allergic inflammation along with TH2 cells by secreting IgE and Ig-fLCs.
Other CD4+ and
CD8+ T cells
Unknown roles.