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T‐cell‐mediated therapeutic strategies are the most potent effectors of cancer immunotherapy. However, an essential barrier to this therapy in solid tumors is disrupting the anti‐cancer immune response, cancer‐immunity cycle, T‐cell priming, trafficking and T‐cell cytotoxic capacity. Thus, reinforcing the anti‐cancer immune response is needed to improve the effectiveness of T‐cell‐mediated therapy. Tumor‐associated protease ADAM10, endothelial cells (ECs) and cytotoxic CD8+ T cells engage in complex communication via adhesion, transmigration and chemotactic mechanisms to facilitate an anti‐cancer immune response. The precise impact of ADAM10 on the intricate mechanisms underlying these interactions remains unclear. This paper broadly explores how ADAM10, through different routes, influences the efficacy of T‐cell‐mediated therapy. ADAM10 cleaves CD8+ T‐cell‐targeting genes and impacts their expression and specificity. In addition, ADAM10 mediates the interactions of adhesion molecules with T cells and influences CD8+ T‐cell activity and trafficking. Thus, understanding the role of ADAM10 in these events may lead to innovative strategies for advancing T‐cell‐mediated therapies. [ABSTRACT FROM AUTHOR]

Trypanosoma cruzi kinetoplastid membrane protein-11 (KMP-11) is able to induce protective immunity in mice. In humans, T-cell immunity during Chagas disease has been documented using parasite antigens allowing the identification of specific CD8+ T cells. However, little is known about the CD4+ T-cell response during the evolution of the disease. In this paper, the induction of a natural CD4+ T-cell response against the KMP-11 protein in T. cruzi infected humans was studied to assess whether this parasite-derived protein could be processed, presented and detected as a major histocompatibility complex class II restricted epitope. The results show that helper T cells from 5 out of 13 chagasic patients specifically produced interferon-γ after exposure to the KMP-11 antigen, whereas healthy donors and non-chagasic cardiopathic patients did not respond. This is the first description of T. cruzi KMP-11 protein recognition by CD4+ T cells in chronic chagasic patients.Immunology and Cell Biology (2009) 87, 149–153; doi:10.1038/icb.2008.76; published online 28 October 2008 [ABSTRACT FROM AUTHOR]

In the early phases of an immune response, T cells of appropriate antigen specificity become activated by antigen-presenting cells in secondary lymphoid organs. Two-photon microscopy imaging experiments have shown that this stimulation occurs in distinct stages during which T cells exhibit different motilities and interactions with dendritic cells (DCs). In this paper, we utilize the Cellular Potts Model, a model formalism that takes cell shapes and cellular interactions explicitly into account, to simulate the dynamics of, and interactions between, T cells and DCs in the lymph node paracortex. Our three-dimensional simulations suggest that the initial decrease in T-cell motility after antigen appearance is due to ‘stop signals’ transmitted by activated DCs to T cells. The long-lived interactions that occur at a later stage can only be explained by the presence of both stop signals and a high adhesion between specific T cells and antigen-bearing DCs. Furthermore, our results indicate that long-lasting contacts with T cells are promoted when DCs retract dendrites that detect a specific contact at lower velocities than other dendrites. Finally, by performing long simulations (after prior fitting to short time scale data) we are able to provide an estimate of the average contact duration between T cells and DCs.Immunology and Cell Biology (2007) 85, 306–314. doi:10.1038/sj.icb.7100054; published online 10 April 2007 [ABSTRACT FROM AUTHOR]

Decisions by uncommitted cells to differentiate down one lineage pathway or another is fundamental to developmental biology. In the immune system, lymphocyte precursors commit to T- or B-cell lineages and T-cell precursors to CD4 or CD8 independently of foreign antigen. T and B cells must also decide whether or not to respond to antigen and when a response is initiated, what sort of response to make such as the type of antibody, CD4 or CD8, and CD4 Th1 or Th2. The two basic mechanisms for these decision-making processes are selection and instruction. Selection depends on prior stochastic production of precommitted cells, which are then selected to respond by an appropriate signal; for example, CD8 and CD4 responses selected by peptide presented in association with major histocompatibility complex class I or II. In contrast, instruction occurs when an uncommitted precursor embarks upon a differentiation pathway in response to a particular set of signals; for example, Th1 and Th2 lineage commitment. In this paper, the signals that determine Th1 and Th2 differentiation are examined with a mathematical model and shown to act as a bistable switch permitting either Tbet or Gata3 to be expressed in an individual cell but not both. The model is used to show how the Tbet Gata3 network within an individual cell interacts with cytokine signals between cells and suggests how Th1 and Th2 lineage commitment can become irreversible. These considerations provide an example of how mathematical models can be used to gain a better understanding of lymphocyte differentiation in an immune response.Immunology and Cell Biology (2007) 85, 300–305; doi:10.1038/sj.icb.7100060; published online 1 May 2007 [ABSTRACT FROM AUTHOR]

The problem with pure recombinant or synthetic antigens used in modern day vaccines is that they are generally far less immunogenic than older style live or killed whole organism vaccines. This has created a major need for improved and more powerful adjuvants for use in these vaccines. With few exceptions, alum remains the sole adjuvant approved for human use in the majority of countries worldwide. Although alum is able to induce a good antibody (Th2) response, it has little capacity to stimulate cellular (Th1) immune responses which are so important for protection against many pathogens. In addition, alum has the potential to cause severe local and systemic side-effects including sterile abscesses, eosinophilia and myofascitis, although fortunately most of the more serious side-effects are relatively rare. There is also community concern regarding the possible role of aluminium in neurodegenerative diseases such as Alzheimer's disease. Consequently, there is a major unmet need for safer and more effective adjuvants suitable for human use. In particular, there is demand for safe and non-toxic adjuvants able to stimulate cellular (Th1) immunity. Other needs in light of new vaccine technologies are adjuvants suitable for use with mucosally-delivered vaccines, DNA vaccines, cancer and autoimmunity vaccines. Each of these areas are highly specialized with their own unique needs in respect of suitable adjuvant technology. This paper reviews the state of the art in the adjuvant field, explores future directions of adjuvant development and finally examines some of the impediments and barriers to development and registration of new human adjuvants. [ABSTRACT FROM AUTHOR]

Summary The CD40-CD40 ligand (CD40L) interaction is one of the most important receptor-ligand interactions that occurs during a T dependent immune response. However, while CD40L is expressed on a range of cell types including activated T cells and B cells, dendritic cells granulocytes, macrophages and platelets, only CD40L on T cells is considered by most immunologists when planning experiments or analysing data. The current theory professes that T cells expressing CD40L can provide signals to B cells that induce proliferation, immunoglobulin class switching, antibody secretion, rescue from apoptosis at different times during the life of a B cell and also has a role in the development of germinal centres and the survival of memory B cells. However, the whole story is more complex than presently understood as human and mouse B cells express CD40L on their surface following activation and can release a soluble form of the ligand. This paper hypothesizes how CD40L on B cells may regulate antibody responses and the development of germinal centres. [ABSTRACT FROM AUTHOR]