The neonatal immune system: modulation by regulatory T-cells and CTLA-4 (CD152)1)

The dysregulation of CTLA-4 (CD152), a glycoprotein expressed on the surface of lymphocytes, may lead to chronic inflammation. Based on the recent scientific findings, it has become clear that CTLA-4 inhibits the effector function and, thus, shuts down the effector phase of T-lymphocytes. Interestingly, the CTLA-4-expressing cells become resistant to apoptosis (programmed cell death) and increasingly migrate to the lymph nodes and tissues. Studies have shown that regulatory T cells (Tregs), which switch off unwanted immune responses can inhibit in vivo only if they express an intact CTLA-4 gene. Moreover, it was confirmed that CTLA-4 is not only expressed on T-lymphocytes but also on B-lymphocytes. The mice with genetic inactivation of CTLA-4 show in B-lymphocytes an increased production of IgM antibodies after immunization. Interestingly, in particular, B- and T-lymphocytes from newborns and infants show a strongly increased CTLA-4 expression, suggesting a key immunoregulatory role in neonatal immune responses. Molecules such as CTLA-4, which regulate the differentiation of lymphocytes, could provide therapeutic targets during the early childhood to set the course for protection against autoimmunity and allergy.

Adult murine hematopoiesis can proceed without β1 and β7 integrins

The function of α4β1 and α4β7 integrins in hematopoiesis is controversial. While some experimental evidence suggests a crucial role for these integrins in retention and expansion of progenitor cells and lymphopoiesis, others report a less important role in hematopoiesis. Using mice with a deletion of the β1 and the β7 integrin genes restricted to the hematopoietic system we show here that α4β1 and α4β7 integrins are not essential for differentiation of lymphocytes or myelocytes. However, β1β7 mutant mice displayed a transient increase of colony-forming unit (CFU-C) progenitors in the bone marrow and, after phenylhydrazine-induced anemia, a decreased number of splenic erythroid colony-forming units in culture (CFUe's). Array gene expression analysis of CD4+CD8+ double-positive (DP) and CD4–CD8– double-negative (DN) thymocytes and CD19+ and CD4+ splenocytes did not provide any evidence for a compensatory mechanism explaining the mild phenotype. These data show that α4β1 and α4β7 are not required for blood cell differentiation, although in their absence alterations in numbers and distribution of progenitor cells were observed.

Cytotoxic differentiation of mouse gut thymodependent and independent intraepithelial T lymphocytes is induced locally. Correlation between functional assays, presence of perforin and granzyme transcripts, and cytoplasmic granules.

Mouse gut intraepithelial lymphocytes (IEL), whether thymodependent (CD4+ or CD8 alpha/beta +; TCR-alpha/beta +) or thymoindependent (CD8 alpha/alpha +; TCR-alpha/beta + or -gamma/delta +), all display cytotoxic activity in a "redirected lysis assay" using anti-CD3 or anti-TCR beta or delta chains secreting hybridomas as targets; this is also observed with IEL of germ-free mice, indicating that this activity, which is absent in peripheral T lymphocytes, does not require stimulation by bacterial antigens. Perforin and granzyme transcripts are detectable in unselected gut IEL, in contrast to normal T lymphocytes of peripheral lymphoid organs. Cytological labeling (with [3H]DFP) of IEL smears reveals labeled granules (i.e., containing serine-esterases, presumably granzymes) in all subsets of gut IEL. This indicates that the gut micro-environment has an inductive role on the cytotoxic differentiation of lymphocytes of various origins when they reach the gut wall to become IEL.

Induction of c-ets and c-fos gene expression upon antigenic stimulation of a T cell hybridoma with inducible cytolytic capacity.

Expression of cellular oncogenes was studied in a T cell hybridoma that undergoes cytolytic activation when stimulated by specific antigen or by anti-Thy-1 antibody. The activation occurs without induction of hybridoma proliferation, providing a model to examine oncogene expression during functional differentiation of lymphocytes. We found that c-fos and c-ets-1 mRNAs were transiently induced at high levels in the hybridoma 30 min and 4 h after stimulation, respectively. c-myc and c-ets-2 oncogenes were constitutively expressed in the hybridoma and their mRNA levels were unaffected during 4 h of stimulation, although c-myc expression was reduced in the later stage of stimulation. Inhibitors of T cell activation, cyclosporin A and anti-LFA-1 antibody, blocked the induction of c-fos and c-ets-1 mRNAs without reducing the levels of c-myc and c-ets-2. The results indicate that the functional activation of the CTL hybridoma is associated with induction of c-fos and c-ets-1 genes.