In this issue of Blood, Pourgheysari and colleagues demonstrate that there is a highly exaggerated expansion of CMV-specific CD4+ T cells in CMV-seropositive compared with CMV-seronegative CLL patients, particularly after chemotherapy.1  Despite this, patient survival is reduced by almost 4 years in the CMV+ cohort. However, as CMV+ CLL individuals do not exhibit symptoms of CMV-induced disease, the negative impact of CMV infection on survival may occur by indirect mechanisms.

CMV-specific T-cell expansion may constrict the T-cell repertoire. (A) Healthy individuals have diverse repertoire of T cells. In CMV-seropositive healthy individuals, there is a disproportionate accumulation of CMV-specific T cells compared with those of other specificities in young but especially in older subjects.6  (B) CMV-seropositive CLL patients have significantly increased proportions of CMV-specific T cells compared with age-matched controls which is even more striking in those who have received chemotherapy.1  One hypothesis for the increased incidence of infections and decreased survival in both CMV-seropositive CLL patients and older humans is that T cells of other specificities (eg, VZV) may be lost through competition for growth factors and or survival niches in tissues.6-8 

CMV-specific T-cell expansion may constrict the T-cell repertoire. (A) Healthy individuals have diverse repertoire of T cells. In CMV-seropositive healthy individuals, there is a disproportionate accumulation of CMV-specific T cells compared with those of other specificities in young but especially in older subjects.6  (B) CMV-seropositive CLL patients have significantly increased proportions of CMV-specific T cells compared with age-matched controls which is even more striking in those who have received chemotherapy.1  One hypothesis for the increased incidence of infections and decreased survival in both CMV-seropositive CLL patients and older humans is that T cells of other specificities (eg, VZV) may be lost through competition for growth factors and or survival niches in tissues.6-8 

Persistent cytomegalovirus (CMV) infection drives the accumulation of CMV-specific T cells (both CD4+ and CD8+), especially in older humans.2  This accumulation of CMV-specific T cells is even more marked in patients with chronic lymphocytic leukemia (CLL) compared with age-matched controls.1  These patients do not experience severe problems like pneumonitis, uveitis, and colitis that can be caused in immunocompromised individuals by this virus.2  Therefore, the anti-CMV T-cell response in CLL patients is sufficient to prevent CMV-induced disease. Although an intense, but asymptomatic, secret battle between CMV and the host also takes place in healthy subjects, CMV seropositivity and the associated large expansion of specific effector T cells also predict decreased survival in older subjects (> 80 years of age).3  Thus, there is a striking parallel between CMV infection in older humans and in CLL patients where infection with this virus in both groups may shorten life expectancy (see figure). However, it is not clear whether the decreased survival is directly due to episodes of CMV reactivation, which seems to be well controlled by specific T cells, or to an indirect effect possibly exerted by the large population of CMV-specific T cells themselves.

Pourgheysari et al speculate that the immunosuppression associated with CLL triggers subclinical viremia that in turn activates and expands CMV-specific T-cell populations.1  In addition, they suggest that chemotherapy may induce increased immune suppression that leads to greater viral reactivation and further expansion of CMV-specific T cells. They were not able to detect CMV reactivation in the blood of CLL patients by polymerase chain reaction, suggesting that viral replication is controlled effectively.1  However, the blood may not be the best place to detect viral reactivation because CMV DNA can be detected in the urine, but not the blood, of older, but not younger, CMV-seropositive subjects.4  Whether CMV DNA is also detectable in the urine of CLL patients remains to be determined. Nevertheless, the reactivation of the virus itself does not seem to be the problem because CLL patients do not exhibit any signs of CMV-induced disease.

CMV-specific CD4+ and CD8+ T-cell populations are both increased in seropositive CLL patients.1,5  One study noted that CMV-specific T cells are driven toward replicative exhaustion suggesting that defects in these cells may develop as a result of continuous viral reactivation.6  Perhaps the expanded cells themselves have the negative impact. The expanded CMV-specific T-cell pool can constitute over 40% of the total CD4+ T-cell repertoire of CLL patients receiving chemotherapy; circumstantial evidence indicates that such expanded T-cell populations can have adverse consequences for immunity. In mice, for example, specific T-cell expansions have been shown to inhibit the function of other antigen-specific T-cell populations and cause disease.7  Furthermore, expanded CMV-specific T cells may inhibit the expansion of Epstein-Barr virus–specific T cells in the same individuals.8  Therefore, there is a possibility that the detrimental effect of CMV infection in CLL patients results from the constriction of the total T-cell repertoire by the overwhelmingly increased numbers of the CMV-specific T-cell population (see figure) because of the competition for essential growth factors and/or overcrowding of tissue niches that support memory T-cell survival. Such an effect would lead to the loss of certain essential memory T-cell populations directed towards other microorganisms. The increased reactivation of latent pathogens (ie, Varicella zoster virus [VZV]) that occurs in CMV-seropositive CLL patients supports this possibility.1  A similar situation may be at work during the aging of healthy CMV-seropositive humans, where accumulation of CMV-specific cells may occlude VZV-specific cells from tissue niches thus leading to the increased incidence of VZV reactivation (shingles) in older humans (see figure).9  A crucial point that requires further investigation is whether the expanded CMV-specific T-cell populations in CLL patients may restrict the quality of the T-cell response to the leukemic cells themselves.

Thus, the study of Pourgheysari et al provides interesting insight into the dominant role that CMV infection has on shaping the T-cell repertoire in CLL patients. Although the exact cause for the negative association of CMV seropositivity and survival in these patients is not currently clear, determining whether targeting the virus itself—or the T-cell expansions that it induces—may improve the survival of both CLL patients and older humans.

Conflict-of-interest disclosure: The author declares no competing financial interests. ■

Acknowledgment

The author thanks Dr Sian Henson and Dr Milica Vukmanovic-Stejic for proofreading and critical comments relating to the article.

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