Association of allergen-specific regulatory T cells with the onset of clinical tolerance to milk protein

J Allergy Clin Immunol. 2009 Jan;123(1):43-52.e7. doi: 10.1016/j.jaci.2008.09.051.


Background: About 70% of children with milk allergy tolerate extensively heated milk (HM) products and outgrow their allergy earlier than those who react to HM.

Objective: To test the hypothesis that HM-tolerant children have a higher precursor frequency of adaptive allergen-specific regulatory T (Treg) cells.

Methods: Allergic, HM-tolerant, outgrown, or control subjects were defined by oral food challenge. PBMCs were cultured with purified caseins and controls for 7 days, and proliferating CD25(+)CD27(+) Treg cells were identified by flow cytometry. Proliferating cells were also characterized for their expression of FoxP3, CTLA 4, CD45RO, and CD127. Allergen-specific Treg cell origin and function were assessed by depletion of CD25(hi) cells before culture.

Results: There was a higher percentage (median [25th% to 75th%], 16.85% [7.1-31.7]) of proliferating allergen-specific CD25(+)CD27(+) T cells from cultures of HM-tolerant subjects (n = 18) than subjects with allergy (n = 8; 4.91% [2.6-7.5]; P < .01). Control subjects with no history of milk allergy (n = 7) also had low percentages of these cells (2.9% [2.4-6.0]), whereas outgrown subjects (n = 7) had intermediate percentages (9.0% [2.7-16.4]). There were no significant differences between the patient groups in the frequency of polyclonal Treg cells or allergen-specific effector T cells. Allergen-specific Treg cells were found to be FoxP3(+)CD25(hi)CD27(+), cytotoxic T lymphocyte-associated antigen 4(+), CD45RO(+)CD127(-) and were derived from circulating CD25(hi) T cells. Depletion of the CD25(hi) cells before in vitro culture significantly enhanced allergen-specific effector T-cell expansion.

Conclusion: A higher frequency of milk allergen-specific Treg cells correlates with a phenotype of mild clinical disease and favorable prognosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Allergens / immunology*
  • Antigens, Differentiation / biosynthesis
  • Antigens, Differentiation / immunology*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Female
  • Gene Expression Regulation / immunology*
  • Humans
  • Immune Tolerance / immunology*
  • Lymphocyte Depletion
  • Male
  • Milk Hypersensitivity / diagnosis
  • Milk Hypersensitivity / immunology*
  • Milk Hypersensitivity / metabolism
  • Milk Hypersensitivity / pathology
  • Prognosis
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism


  • Allergens
  • Antigens, Differentiation