Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation.

Abstract

SummaryNeonatal thymectomy (NTx), especially around day 3 after birth, causes various organ-specific autoimmune diseases in mice. This report shows that: (a) T cells expressing the interleukin 2 receptor cx chains (CD25) ontogenically begin to appear in the normal periphery immediately after day 3, rapidly increasing within 2 wk to nearly adult levels (~10% of CD3 + cells, especially ofCD4 + cells); (b) NTx on day 3 eliminates CD25 + T cells from the periphery for several days; inoculation immediately after NTx of CD25 + splenic T cells from syngeneic non-Tx adult mice prevents autoimmune development, whereas inoculation of CD25-T cells even at a larger dose does not; and furthermore, (c) similar autoimmune diseases can be produced in adult athymic nu/nu mice by inoculating either spleen cell suspensions from 3-d-old euthymic nu/+ mice or CD25 + cell-depleted spleen cell suspensions from older, even 1-yr-old, nu/+ mice. The CD25-populations from neonates or adults are also similar in the profile of cytokine formation. These results, taken together, indicate that one aspect of peripheral self-tolerance is maintained by CD25 + T ceils that sustain potentially pathogenic self-reactive T ceils in a CD25-dormant state; the thymic production of the former is developmentally programmed to begin on day 3 after birth in mice. Thus, NTx on day 3 can, at least transiently, eliminate/ reduce the autoimnmne-preventive CD25 + T cells, thereby leading to activation of the selfreactive T ceils that have been produced before NTx.

Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy

“…The role of Treg cells in maintaining immunological tolerance to self-Ags has been illuminated, in part, through adoptive transfer experiments. A spectrum of tissue-specific autoimmune diseases, including thyroiditis, oophoritis, gastritis and inflammatory bowel disease, occurs when immunodeficient mice are transfused with T cells depleted of CD4 + CD25 + cells [52,53]. The concomitant transfer of Treg cells abrogates development of these autoimmune diseases.…”

Resting B cells expand a CD4+CD25+Foxp3+ Treg population via TGF‐β3

“…There are also strong evidences for the generation of CD4 1 CD25 1 Foxp3 1 Treg in the periphery. Experiments carried out in thymectomized or RAG-2-deficient mice lacking CD4 1 CD25 1 T cells show that nTreg can be generated in the periphery from CD4 1 CD25 À T cells [11,12].In addition to co-stimulation via the B7-CD28 and TCR-MHC class II pathways, various cytokines such as IL-2, TGF-b1 and IL-10 have been associated with the generation of peripheral Treg. IL-2 and IL-2R knockout mice have few, if any, nTreg and develop severe lymphoproliferation and autoimmunity [13,14].…”

Autologous umbilical cord blood infusion for type 1 diabetes

“…[17]. In terms of the cellular basis for this immunoregulatory failure, it is key to note (albeit somewhat controversial) that both NOD mice and patients with T1D have potential deficiencies in at least two T cell populations intimately involved in immune regulation; NKT cells and CD4+CD25+ or so called "regulatory" T cells (Treg) [18][19][20][21][22]. In addition to defects in T cell based immune regulation, developmental and functional defects have also been reported in B-lymphocytes as well as antigen presenting cells (APC) of both NOD mice and human's with T1D; including those of differentiation and function of macrophages and DC [23][24][25][26][27][28][29].…”

“…Nevertheless, morbidity was still an issue. Male patients had semen samples stored prior to treatment to preserve fertility, all patients received antimicrobial and antifungal prophylaxis, mean hospital stay was 19.2 days (range [15][16][17][18][19][20][21][22][23][24], and nearly all patients experienced the common transplantationrelated complications of febrile neutropenia, nausea, vomiting, and alopecia.…”