In contrast to earlier reports, the reduced

Treg compartment of mice lacking cDC or selective CD80/86 expression on cDC, as such, did not render the respective animals prone to systemic lymphocyte hyperactivation or autoimmunity. Rather, we provide evidence that elevated immunoglobulin titers, as well as changes in T-cell subset prevalence and activation status are strictly associated with the nonmalignant myeloproliferative disorder triggered by the absence of cDC. Productive T-cell activation requires, in addition to the TCR stimulus, a second signal provided by costimulatory molecules, the best characterized of which are CD80 (B7-1) and CD86 (B7-2). CD80 and CD86, which are expressed mainly on B cells, Sorafenib clinical trial DC and medullary thymic epithelial cells (mTEC) 1, are the only known ligands of CD28 and CTLA-4 receptors on T cells. Functions of CD28 and CTLA-4 are distinct learn more with CD28 promoting T-cell activation and CTLA-4-negative regulating T-cell responses. Peripheral self-tolerance and immune homeostasis are maintained, at least in part, by a delicate balance of T effector and Treg. CD25+CD4+ Treg, which arise spontaneously as the so-called natural Treg

(nTreg) in the thymus, express the transcription factor forkhead box P3 (Foxp3) and can suppress the activation and proliferation of T lymphocytes in multiple ways. In addition, naïve T cells can also acquire Foxp3 expression in the periphery in the course of immune responses yielding inducible Treg with suppressive activity. Foxp3+ Treg, whether thymus derived or induced in the periphery, constitutively express both CTLA-4 and CD28 2. Moreover, CD80/86–CD28/CTLA4 interactions are required for the development, maintenance and function of Treg 3–6. Thus, the absence of CD80/86 results in a severe reduction of thymic Treg with no apparent changes in the percentages and distribution of conventional T-cell subsets 4. Furthermore, animals treated with B7-blocking antibodies and CD28-deficient

RVX-208 mice display a markedly reduced Treg compartment 3–6. Available data suggest that both radio-resistant mTEC and BM-derived hematopoetic cells can deliver costimulatory signals that promote Treg generation in the thymus through CD80/86 interactions, with hematopoetic cells being more efficient 7. In addition to their role in thymic Treg development, B7 interactions are also required to maintain the peripheral Treg compartment 3. Thus, administration of anti-CD80/86 antibodies reduces the percentage of peripheral Treg even in thymectomized mice lacking nTreg 4. Furthermore, adoptively transferred Treg show a reduced turnover in recipient mice subjected to B7-blockade 4, 8 and conversion of polyclonal naïve T cells into Foxp3+ Treg was found to be abrogated in B7-deficient recipient animals 9.