Hematologic cancers pose a unique challenge to the immune system, as they can present their antigens both directly to host T cells, or indirectly following transfer to host ARC, with fundamentally distinct signals accompanying each mode of presentation. For naive CD8+ T cells, the outcome of these events can determine whether an effective anti-tumor response is either induced, or rendered functionally silent through a variety of tolerance mechanisms. There are currently significant gaps in both our understanding of the antigen-presenting cells (APC) capacity of normal B cells or their transformed counterparts, lymphomas and myelomas, as well as the consequences of this for primary antigen-specific CD8+ T cells of in vivo. This application, based on a robust experimental model and supported by strong preliminary data, proposes the hypothesis that under physiological conditions, normal B cells efficiently program a durable state of tolerance in naTve CD8+ T cells through a novel mechanism involving transmission of signals that lead to primary expansion and subsequent uncoupling of the TCR proximal signaling machinery from the downstream cytotoxic effector functions in the clonal progeny. We further suggest that this same pathway is utilized by lymphomas to purge the available CD8+ T cell repertoire of clones capable of recognizing the multitude of antigens that arise during the process of transformation. The objective of this research is therefore to understand how normal and transformed primary B cells induce tolerance in CD8+ T cells under physiological conditions in vivo. Using a novel in vivo transgenic system that features expression of a model antigen on primary B cells, we will pursue the following aims:
Aim 1) to characterize of the exact pathways in which B cells induce CD8+ T cell tolerance, Aim 2) to define the molecular defect underlying the tolerant phenotype of CDS T cells, Aim 3) to determine whether spontaneous lymphomas induce CD8+ T cell tolerance via the same pathway, and Aim 4) to establish methods through which the induction of CDS T cell tolerance by B cells can be prevented or overcome. The results of these studies will shed important new light on the APC function of normal and transformed B cells, and will allow the development of much-needed new strategies for enhancement of immune responses to B cell tumors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI076972-04
Application #
7881625
Study Section
Special Emphasis Panel (ZRG1-CII-V (01))
Program Officer
Lapham, Cheryl K
Project Start
2007-06-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$453,692
Indirect Cost
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Feau, Sonia; Schoenberger, Stephen P; Altman, Amnon et al. (2013) SLAT regulates CD8+ T cell clonal expansion in a Cdc42- and NFAT1-dependent manner. J Immunol 190:174-83
Feau, Sonia; Garcia, Zacarias; Arens, Ramon et al. (2012) The CD4? T-cell help signal is transmitted from APC to CD8? T-cells via CD27-CD70 interactions. Nat Commun 3:948
Wolkers, Monika C; Gerlach, Carmen; Arens, Ramon et al. (2012) Nab2 regulates secondary CD8+ T-cell responses through control of TRAIL expression. Blood 119:798-804
Arens, Ramon; Loewendorf, Andrea; Redeker, Anke et al. (2011) Differential B7-CD28 costimulatory requirements for stable and inflationary mouse cytomegalovirus-specific memory CD8 T cell populations. J Immunol 186:3874-81
Feau, Sonia; Arens, Ramon; Togher, Susan et al. (2011) Autocrine IL-2 is required for secondary population expansion of CD8(+) memory T cells. Nat Immunol 12:908-13
Arens, Ramon; Loewendorf, Andrea; Her, Min J et al. (2011) B7-mediated costimulation of CD4 T cells constrains cytomegalovirus persistence. J Virol 85:390-6
Rozanski, Cheryl H; Arens, Ramon; Carlson, Louise M et al. (2011) Sustained antibody responses depend on CD28 function in bone marrow-resident plasma cells. J Exp Med 208:1435-46
Nierkens, Stefan; den Brok, Martijn H; Garcia, Zacharias et al. (2011) Immune adjuvant efficacy of CpG oligonucleotide in cancer treatment is founded specifically upon TLR9 function in plasmacytoid dendritic cells. Cancer Res 71:6428-37
Feau, Sonia; Schoenberger, Stephen P (2011) From the loading dock to the boardroom: a new job for Akt kinase. Immunity 34:141-3
Arens, Ramon; Schoenberger, Stephen P (2010) Plasticity in programming of effector and memory CD8 T-cell formation. Immunol Rev 235:190-205

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