The immune system is not supposed to react to self-antigens (tolerance) but does recognize and eliminate non-self antigens (immunity). However, over reaction of the immune system to non-self antigens can cause diseases termed hypersensitivity. Contact hypersensitivity (CHS) is a T cell mediated delayed type hypersensitivity response to haptens in the skin. Dendritic cells (DC) are prominent antigen presenting cells for the induction of CHS responses. However, less is known about DC mediated suppressive mechanisms in the immune response. CD5 is a surface molecule which is expressed by T cells and DC. It is well known that CD5 mediates inhibitory signals for T cells and plays important roles in immune tolerance. However, it is unexplored whether CD5 expressed on DC has a role in DC mediated immune regulations. Our preliminary studies have showed that CD5 is expressed by CD11c+ myeloid and lymphoid DC from spleen, lymph node and thymus whereas it is not detectable in plasmacytoid DC. Transfer of hapten labeled CD11c+ DC from CD5 gene knockout (CD5-/-) mice induces a significant higher level of CHS responses than wild type DC. Correspondingly, hapten primed T cells from CD5-/- DC sensitized mice produce higher levels of inflammatory cytokines than those from wild type DC sensitized animals. Further experiments show that CD5-/- DC are more potent than wild type DC to activate CD4+ and CD8+ T cells and induce anti-tumor immunity. These data have for the first time demonstrated that CD5 molecules expressed on DC have an inhibitory effect on DC functions in the activation of T cells and induction of immune responses. The hypothesis of the current application is that the CD5-CD5 interaction between DC and T cells inhibits T cell activation and is an important mechanism for DC induced immune suppression.
Three specific aims are proposed to examine the hypothesis.
Aim 1 is to determine whether CD5 is an inhibitory molecule for DC mediated activation of T cells and induction of immune responses. We will examine whether restoration or over-expression of CD5 by CD5-/- DC inhibits their functions and renders DC tolerogenic. We will also examine whether an effect of CD5 on the development of T cell subpopulations is a mechanism for DC CD5 mediated effects on immune responses.
Aim 2 will determine whether CD5 molecules expressed on DC have an inhibitory effect on effector T cells and regulate the elicitation of immune responses. We will examine mechanism by which CD5 expressed on DC regulates effector T cells and whether application of DC with a high level of CD5 expression can desensitize hapten sensitized animals to hapten challenge.
Aim 3 will examine mechanisms by which CD5 expressed on DC inhibits T cell activation and DC function. We will determine whether CD5 is a homotypic ligand for CD5 mediated suppression of T cell activation or CD5 mediated signals in DC are responsible for the suppression of DC functions. The outcome of the proposal will yield new insights into a novel role of CD5 in DC mediated immune regulations, advance our understandings of immune pathogenesis for hypersensitivity diseases, and provide important information for development of new therapeutic strategies.

Public Health Relevance

CD5 is a membrane protein that mediates inhibitory signals for T lymphocyte activation and plays important roles in inflammatory immune diseases. Antigen presenting dendritic cells are required for the activation of T lymphocytes and induction of immune responses. It is unknown whether CD5-CD5 interactions between antigen presenting dendritic cells and T lymphocytes regulate immune responses. The current proposal will determine whether the expression level of CD5 by antigen presenting dendritic cells is related to their ability to inhibit the function of lymphocytes in immune responses. The outcome will elucidate a novel mechanism for CD5 mediated immune suppression in inflammatory diseases and may be exploited to new therapeutic strategies.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Exploratory/Developmental Grants (R21)
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Innate Immunity and Inflammation Study Section (III)
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Cibotti, Ricardo
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University of Alabama Birmingham
Schools of Medicine
United States
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