Immunodeficiency in early CLL and other lymphomas

There is a mystery as to why indolent lymphomas become immunodeficient. Oh, I know about the low immunoglobulins, but it is apparent that not just CLL, but myeloma and other types of lymphoma all fail to respond well to immunization with vaccines. Response to vaccines is generally a T-cell responsibility, so what's gone wrong with the T cells?

A paper in this week's Blood addresses the problem. Reduced T cell counts are common in the untreated indolent lymphoid tumors and there is an almost universal pattern of unresponsiveness to vaccination against Hepatitis B. They identified two different patterns of dysregulation of the T-helper cell compartment.

Pattern 1: chronic immune activation with Th2 shift, in vitro hyperreactivity and T cell senescence with propensity to undergo apoptosis.

This exists in follicular lymphoma and extranodal marginal zone lymphomas. This is characterized by a marked reduction of naive T-helper cells and recent thymus emigrants. There is an activated T helper phenotype and a Th2 shift (a tendency to make IL-4 rather than IL-2). It seems that naive T cells are attracted to lymphoma sites and reprogrammed to make IL-4 by cytokines such as CCL17 and CCL22. Activated T cells (CD69+ of OX40+ T helper cells) are absent from the peripheral blood but abound at lymphoma sites. Some of these are aberrantly activated and return to the circulation where they are sensitive to activation via the TCR or CD28. These cells are prone to apoptosis. These processes act together to decrease the numbers of T helper cells available for immune reactions.

This pattern may be seen in late CLL but not in early CLL. It may also be seen in some inflammatory conditions such as SLE and rheumatoid arthritis and in some elderly persons.

The second pattern: down regulation of TCR signaling and cytokine secretion. This pattern is characterized by a reduced expression of multiple genes associated with co-stimulation of the TCR and CD28 resulting in a reduced secretion of cytokines. Among the genes under-expressed are those of the NFkappaB and PI3K pathways. A consequence of this type of T-cell dysfunction is severely impaired formation of the immunological synapse and as well as in early stage CLL it is seen in the leukemia phase of follicular lymphoma. It can be induced in normal T cells by contact with CLL cells.

There does not seem to be a role for Tregs in either pattern. Previous reports of relative increases of Tregs in indolent lymphoma, early CLL and MGUS appear to be due to an absolute reduction in naive T helper cells.