In healthy adults, the immune system maintains a repertoire of T and B lymphocytes that recognize and eliminate infecting microorganisms and yet remain unresponsive toward the host's own cells and tissues. The goal of the Caton laboratory is to define the mechanisms by which B cells and T cells that "recognize" the body's own tissues and cells (autoreactive) are regulated and to understand how these processes fail and/or can be manipulated in autoimmune diseases like lupus and cancer.
To examine these questions the laboratory has analyzed immune response to influenza virus in great detail, and has generated transgenic mice that express a well-characterized antigen from influenza virus called HA, using a variety of promoters to direct HA expression in different cells and tissues. The researchers have shown that variations in the expression of HA in different transgenic mouse lineages can cause CD4+ T cells with identical specificity for a self-peptide either to be deleted (to varying degrees); to undergo selection to become CD4+ CD25+ regulatory T cells; or to become auto-aggressive, that is "attack" the body's own tissues and cells. The Caton laboratory has contributed to the considerable recent interest in the role that regulatory T cells, especially CD4+ CD25+ regulatory T cells, can play in preventing autoimmunity. They and others firmly established the existence of cell populations that prevent immune responses to host cells and tissues. The laboratory has also analyzed how autoreactive B cells that can recognize self-antigens are regulated and/or can become activated either by viral infection or spontaneously through failures to adequately regulate autoreactive CD4+ T cells. Studies in this system allow the Caton laboratory to define parameters that dictate how the immune system interacts with virus and self-antigens, and to develop approaches for preventing or augmenting these responses in different therapeutic settings.
Recent Scientific Advances
Regulation of autoreactive CD4+ T cells
The Caton Laboratory has been examining how CD4+CD25+ regulatory T cells are instructed to undergo selection in response to self-peptides. In particular, how variations in the cell types and/or amounts with which peptides are expressed in different cell types was examined using transgenic mice expressing the influenza virus hemagglutinin (HA) under the control of several different promoters. Major conclusions from these studies were that regulatory T cell formation and deletion of autoreactive CD4+ T cells can take place simultaneously during thymic development, and that processes acting in the periphery can also contribute to CD25+ T cell repertoire formation. In recent studies his laboratory has been examining how TCR specificity directs regulatory T cell function in vivo.
Specificity of regulatory T cell function
Dr. Caton’s laboratory previously used transgenic mouse systems to show that CD4+CD25+Foxp3+ regulatory T (Treg) cells can undergo both thymic selection and peripheral expansion in response to self-peptides that are agonists for their T cell receptors (TCRs). However, the specificity by which these TCRs must recognize peptide:MHC complexes in order to activate Treg cell function was not known. They have now shown that CD4+CD25+Foxp3+ Treg cells can mediate suppression in response to peptides that are only weakly crossreactive with the self-peptide that induced their formation in vivo. Moreover, suppression could be efficiently activated by peptide analogs that were inefficient at inducing CD69 upregulation, and that also induced little or no proliferation of naïve CD4+CD25-Foxp3- T cells expressing the same TCR. These findings provide evidence that self-peptide-specific CD4+CD25+Foxp3+ Treg cells can exert regulatory function in response to self-peptides with which they are only weakly crossreactive, which may contribute to the ability of Treg cells to modulate anti-tumor immune responses in infection and in cancer.
Regulation of autoreactive memory B cell formation
Previous studies from the Caton laboratory have shown that some autoreactive B cells routinely evade negative selection during immune repertoire formation and can be activated to produce antibodies by virus immunization. They have also shown that the fate of these cells can vary during the processes of B cell memory formation, during which B cells undergo somatic mutation and acquire higher affinities for eliciting antigens. To show this, they examined the fate of HA-specific B cells in different lineages of transgenic mice that express the HA in different amounts and cell types. In some lineages (e.g. HA104 mice), the formation of HA-specific memory B cells is unaffected by the presence of the HA self-antigen, and high titers of somatically mutated high affinity anti-HA antibodies (that are potentially self-reactive) can be induced by virus immunization. In other cases (e.g. HACII mice, in which HA is expressed at high levels by various cells, including B cells themselves), these HA-specific B cells can be negatively selected during the processes of memory B cell formation by a B cell intrinsic, specificity-based mechanism.
Most recently, the Caton Laboratory has examined the formation of autoreactive memory B cells in PevHA mice, which express the HA driven by a b-globin locus control region. Using a virus immunization strategy, they showed that PR8 HA-specific memory B cell formation can occur in PevHA mice, even though a major subset of PR8 HA-specific B cells is negatively selected from the primary repertoire. They also showed PR8 HA-specific memory B cells develop spontaneously in TS1xPevHA mice, which co-express a transgenic PR8 HA-specific TCR and contain a high frequency of HA-specific CD4+ T cells but have not been subjected to virus immunization. Notably, autore active memory B cell formation occurred in TS1xPevHA mice even though approximately half of the HA-specific CD4+ T cells were CD25+Foxp3+ cells that could significantly attenuate, but did not completely abolish HA-specific autoantibody production in an adoptive transfer setting. The findings provide evidence that a high frequency of autoreactive CD4+ T cells can be sufficient to promote autoreactive memory B cell formation in the absence of signals provided by overt immunization or infection, and despite the presence of abundant autoantigen-specific CD4+ CD25+ Foxp3+ regulatory T cells.