Perforin-dependent cytotoxic activity and lymphokine secretion by CD4+ T cells are regulated by CD8+ T cells

ArticleinThe Journal of Immunology 159(5):2091-9 · October 1997with8 Reads
Source: PubMed
Factors influencing the development of CD4+ T cell subpopulations with differing lymphokine profiles are well established. However, CD4+ cells can show both perforin- and Fas ligand-dependent cytotoxicity, and little is known about conditions favoring the development of these effector activities. We now report that CD8+ cells regulate the development of perforin-dependent cytotoxicity in CD4+ cells. CD4+ cells activated in either the presence or absence of CD8+ cells developed Fas ligand-dependent cytotoxic activity. However, CD4+ cells developed perforin-dependent cytotoxicity only in the absence of activated CD8+ cells. CD8+ cells also inhibited the development of IL-4-secreting CD4+ cells; however, there was no correlation between the expression of perforin-dependent cytotoxic activity and the ability to secrete IL-4, and perforin-dependent cytotoxic CD4+ cells represented only 10% of isolated clones. This suggests that the two characteristics are expressed in different CD4+ subsets and might be regulated by distinct effects of the CD8+ cells. In keeping with this, regulation of the lymphokine profile of CD4+ cells by CD8+ cells was consistent with mediation by IFN-gamma, but only when delivered at high concentrations requiring close proximity of the cells. In contrast, regulation of perforin-dependent cytotoxic activity of CD4+ cells by CD8+ cells seemed inconsistent with an IFN-gamma-dependent mechanism, suggesting either direct cell contact or close proximity to allow delivery of an unidentified soluble factor. The characteristics of perforin-dependent CD4+ CTL and their regulation by activated CD8+ cells suggest that they represent a previously unrecognized subpopulation that plays a defensive role when a CD8+ cell response is absent.
    • "Previous examinations have shown that the frequency of CD4 + cytotoxic T cells is partially increased in a subset of patients with chronic HBV infection, but not to the extent in HCC patients [12,27]. Studies have also shown that CD4 + T cells produce perforin only in the absence of CD8 + T cell cytotoxicity [28]. And they are found in chronic viral infections (such as HIV and LCMV) that possess the ability to suppress MHC class I antigen presentation [7]. "
    [Show abstract] [Hide abstract] ABSTRACT: Hepatocellular carcinoma (HCC) is a common cancer with poor prognosis and low five-year survival rate. A strong and effective CD4+ T cell-mediated cytotoxicity was associated with better survival and low recurrence rate in HCC, but the regulatory mechanism that controls CD4+ T cell cytotoxicity in HCC patients is not fully examined. Given that IL-10-expressing B cells could suppress the inflammation of cytotoxic CD8+ T cells, T helper 1 (Th1) cells and Th17 cells, while promoting regulatory T (Treg) cell differentiation, we examined the role of IL-10-expressing B cells in HBV-related HCC patients. We found that compared to healthy controls, HCC patients exhibited significantly higher frequencies of IL-10-expressing B cells, which were negatively correlated with the frequencies of granzyme A, granzyme B, and perforin expressing CD4+ T cells. Surface molecule Tim-1 was preferentially expressed on IL-10-expressing B cells. Therefore, we separated total B cells into Tim-1+ and Tim-1- B cells. CD4+ T cells incubated with Tim-1+ B cells exhibited significantly reduced levels of granzyme A, granzyme B and perforin expression, compared to the CD4+ T cells incubated with Tim-1- B cells. Antagonizing IL-10 in culture rescued CD4+ T cell cytotoxicity. Compared to that in peripheral blood, the level of IL-10-expressing B cells were further upregulated in resected tumor, while the level of CD4+ cytotoxic T cells was downregulated. The negative correlations between IL-10-expressing B cells and CD4+ cytotoxic T cells were also observed in tumor-infiltrating cells. Together, our data revealed an additional antitumor mechanism mediated by IL-10-expressing B cells.
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    • "One of the challenges of identifying ThCTL in situ is that they are overshadowed and seemingly inhibited by the presence of CD8 CTL which outnumber them [29, 30]. Thus it is not surprising that ThCTL have also been identified in virally infected mice deficient in, or depleted of, CD8 T cells. "
    [Show abstract] [Hide abstract] ABSTRACT: CD4 T cells that acquire cytotoxic phenotype and function have been repeatedly identified in humans, mice, and other species in response to many diverse pathogens. Since CD4 cytotoxic T cells are able to recognize antigenic determinants unique from those recognized by the parallel CD8 cytotoxic T cells, they can potentially contribute additional immune surveillance and direct effector function by lysing infected or malignant cells. Here, we briefly review much of what is known about the generation of cytotoxic CD4 T cells and describe our current understanding of their role in antiviral immunity. Furthering our understanding of the many roles of CD4 T cells during an anti-viral response is important for developing effective vaccine strategies that promote long-lasting protective immunity.
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    • "The finding of both IpCD4L-1 and IpCD4L-2 message in TS32.17 cells implies that catfish have cytotoxic CD4 + CTL with the caveat being that one or both of these molecules may have CD4 function. In mammals, CD4 + CTL have been shown in vitro to use the same cytolytic pathways as CD8 + CTL5960616263. However, the importance of CD4 + CTL still remains unclear. "
    [Show abstract] [Hide abstract] ABSTRACT: Two CD4-like (CD4L) molecules have been identified in channel catfish, Ictalurus punctatus. Although phylogenetically related to other vertebrate CD4 molecules, they exhibit only 19% amino acid identity to each other. IpCD4L-1 encodes a predicted protein containing four immunoglobulin domains, a transmembrane region and a cytoplasmic tail containing a p56(lck) binding site. In contrast, IpCD4L-2 encodes for a similar protein with three immunoglobulin domains. The gene organization of IpCD4L-1 is very similar to that of other vertebrate CD4 genes, while the genomic organization of IpCD4L-2 is different. Southern blots indicate both catfish molecules are likely single copy genes and mapping studies show that both are found on a single Bacterial Artificial Chromosome suggesting close linkage. At the message level, IpCD4L-1 and -2 are expressed in various catfish lymphoid tissues and in non-B-cell peripheral blood leukocytes (PBL). Both messages are upregulated in concanavalin A (ConA) and alloantigen stimulated PBL, but not in lipopolysaccharide (LPS)-stimulated cultures. In contrast, they are differentially expressed among the catfish clonal T cell lines. While both molecules appear to be T cell specific, their functional significance in catfish is unknown.
    Full-text · Article · Feb 2007
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