T Cells Prevent the Development of Spontaneous B-cell Lymphomas

Inactivating mutations in the plasma cell differentiation gene BLIMP1 (also known as PRDM1) and activating mutations in the transcriptional regulator BCL6 are frequent in diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma, but healthy individuals can harbor such mutations without signs of disease. In addition to pointing to a requirement for additional mutations, this observation is consistent with the possibility that the immune system can remove transformed B cells and prevent cancer growth. Afshar-Sterle and colleagues established that T cells have a critical role in this immune surveillance mechanism because T cell–sufficient mice with B cell–specific deletion of Blimp1 failed to develop lymphoma, whereas T cell–deficient mice succumbed to DLBCL-like disease. Similarly, T cell–deficient Bcl6-transgenic mice, but not their T cell–sufficient counterparts, rapidly developed lymphoma with complete penetrance. Restoration of the polyclonal CD8⁺ T-cell population specifically restricted lymphoma formation in immunodeficient mice injected with DLBCL-specific lymphoma cells, identifying CD8⁺ cells as the cell population most likely responsible for T-cell mediated lymphoma surveillance. The control of B-cell lymphomas by CD8⁺ T cells depended on costimulation and specific antigen recognition, and yet, several mechanisms common to CD8⁺ T-cell function were dispensable, such as perforin and granzymes. Interestingly, CD8⁺ T cells lost their ability to control B-cell lymphoma cell growth in the absence of Fas ligand signaling, suggesting one mechanism that CD8⁺ T cells use to impede spontaneous B-cell lymphoma development and raising the possibility that suppression of Fas ligand expression could represent a way for B-cell lymphomas to escape immune surveillance. Although it remains unclear how CD8⁺ T cells recognize transformed B cells, these data provide direct evidence of a T-cell mediated immune surveillance mechanism that prevents lymphoma development.

Afshar-Sterle S, Zotos D, Bernard NJ, Scherger AK, Rödling L, Alsop AE, et al. Fas ligand-mediated immune surveillance by T cells is essential for the control of spontaneous B cell lymphomas. Nat Med 2014 Feb 2 [Epub ahead of print].