Professional antigen-presenting cells (APCs) are capable of transporting self-antigens from peripheral tissues to secondary lymphoid organs where they are presented to potentially autoreactive CD8+ T cells. In the absence of an inflammatory response, this results in immune tolerance. The presence of activated, antigen-specific CD4+ T cells converts this tolerogenic encounter into an immunogenic one by promoting extensive proliferation of CD8+ T cells and their development into effectors. Surprisingly, activation of APCs with an agonistic antibody specific for CD40 could not substitute for CD4+ help in this task. Anti-CD40 induced recruitment of dendritic cells expressing high levels of B7 costimulatory molecules into the lymph nodes, which in turn, greatly enhanced activation and expansion of CD8+ T cells. However, these activated CD8+ cells did not demonstrate effector function. We conclude that proliferative potential and gain of effector function are separable events in the differentiation program of CD8+ T cells.

We conclude that the risk of primary CMV infection is a continuous lifelong event and correlates with age and female gender.

A single nucleotide polymorphism in the protein tyrosine phosphatase nonreceptor type 22 gene (PTPN22), that encodes the Lyp tyrosine phosphatase LypR620W, has been linked to a number of autoimmune diseases including type I diabetes, rheumatoid arthritis and systemic lupus erythematosus. Studies in PTPN22 KO mice and in mice expressing the mouse homolog of the pro-autoimmune allele, PepR619W, have reported increased germinal center activity and enhanced antibody production. Here we present findings that explain the basis for increased germinal center activity in PTPN22 mutant mice. As compared with their wild type equivalents, TFH cells from PTPN22 KO mice proliferate and accumulate to a greater extent, and exhibit enhanced production of IL-21. The follicular regulatory T cells (TFR) in PTPN22 KO mice do not expand to effectively regulate these TFH cells, resulting in an increase in B cell numbers and antibody production. This is evident in the KBxN mouse model of arthritis in which PTPN22 deficiency results in increased severity of disease. Our findings demonstrate the importance of cell type specific PTPN22 activity on regulation of antibody production.

Weak T-cell antigen receptor (TCR)-ligand interactions are sufficient to activate naïve CD8+ T cells, but generally do not result in tumor eradication. How differences in TCR affinity affect the regulation of T-cell function in an immunosuppressive tumor environment has not been investigated. We have examined the functional differences of high- vs. low-affinity CD8+ T cells and we observed that infiltration, accumulation, survival and cytotoxicity within the tumor are severely impacted by the strength of TCR-ligand interactions. In addition, high-affinity CD8+ T cells were found to exhibit lower expression of inhibitory molecules including PD-1, LAG-3 and NKG2A, thus being less susceptible to suppressive mechanisms. Interferon γ and autocrine interleukin-2 were both found to influence the level of expression of these molecules. Interestingly, although high-affinity CD8+ T cells were superior to low-affinity CD8+ T cells in their ability to effect tumor eradication, they could be further improved by the presence of tumor specific CD4+ T cells. These findings illustrate the importance of both TCR affinity and tumor-specific CD4 help in tumor immunotherapy.

A major challenge in tumor immunology is how best to activate the relatively low avidity self-specific and tumor-specific T cells that are available in the self-tolerant repertoire. To address this issue, we produced a TCR transgenic mouse expressing a class I-restricted hemagglutinin (HA)-specific TCR (clone 1 TCR) derived from a mouse that expressed HA as a self-Ag in the insulin-producing β cells of the pancreatic islets (InsHA) mice. Upon transfer of clone 1 TCR CD8+ T cells into InsHA mice, very few cells were activated by cross-presented HA, indicating that the cells were retained in InsHA mice because they ignored the presence of Ag, and not because they were functionally inactivated by anergy or tuning. Upon transfer into recipient mice in which HA is expressed at high concentrations as a tumor-associated Ag in spontaneously arising insulinomas (RIP-Tag2-HA mice), a high proportion of clone 1 cells were activated when they encountered cross-presented tumor Ag in the pancreatic lymph nodes. However, the activated cells exhibited very weak effector function and were soon tolerized. The few activated cells that did migrate to the tumor were unable to delay tumor progression. However, when HA-specific CD4 helper cells were cotransferred with clone 1 cells into RIP-Tag2-HA recipients and the mice were vaccinated with influenza, clone 1 cells were found to exert a significant level of effector function and could delay tumor growth. This tumor model should prove of great value in identifying protocols that can optimize the function of low avidity tumor-specific T cells.