The NK cell as a new player in the pathogenesis of HTLV-I associated neurologic disease

Human T-cell lymphotropic virus type I (HTLV-I) is an exogenous human retrovirus that has been demonstrated to be the etiologic agent in adult T cell leukemia and a progressive neurological disease termed HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP).^1,2 HAM/TSP is caused by preferential damage of the thoracic spinal cord and is characterized clinically by muscle weakness, hyperreflexia, and spasticity in the lower extremities, and urinary disturbance. It has clinical similarities to the primary progressive form of multiple sclerosis.³ Although development of HAM/TSP is not completely understood, virus-host immunological interactions have been suggested to play a role in the pathogenesis of this disorder.⁴

A number of immunological functions have been shown to be elevated in patients with HAM/TSP, including high frequencies of circulating HTLV-I-specific CD8+ cytotoxic T lymphocytes (CTL), high antibody titers against HTLV-I antigens in both peripheral blood and cerebrospinal fluid, and an increased expression of cytokine and chemokines.⁵ The immunological hallmark of HTLV-I infected individuals is the capacity of PBMC to spontaneously proliferate in vitro,⁴ i.e., extraordinarily high uptake of 3H-thymidine (typically greater than 100,000 cpm after 4 days in culture) in the absence of exogenous antigens or stimulants. Moreover, the magnitude of this spontaneous lymphoproliferation is more pronounced in HAM/TSP patients than in asymptomatic HTLV-I carriers and has been used as an evaluation of treatment for this disorder.⁶ Since HTLV-I proviral load is typically higher in patients with neurologic disease than in carriers, as with other immunologic parameters, it has been suggested that the high virus loads drive spontaneous proliferation. However, it is still unknown if this spontaneous proliferation is solely a consequence of activation of CD4+ HTLV-I-infected T-cells or may in part be due to expansion of CD8+ virus-specific lymphocytes.

Although HTLV-I has a preferential tropism for CD4+ T-cells in vivo other peripheral blood cells have also shown to harbor HTLV-I including CD8+ cells, and more recently, CD14+ macrophages⁷ and dendritic cells.⁸ The tax region of HTLV-I encodes the Tax protein, a strong transactivator of both viral and host genes, including IL-2 and IL-2 receptor (IL2r) and it has been suggested that the high spontaneous proliferation demonstrated from PBMC of HAM/TSP patients may be due to HTLV-I-infected CD4+ T-cells proliferating by an IL2-IL2r autocrine loop in vitro.⁹ Additionally, spontaneous proliferation of specific cell subsets has been examined directly from PBMC of HAM/TSP patients. Using purified cell separation techniques, spontaneous proliferation was observed in T-cells but not in B-cells or monocytes.¹⁰ Although, CD4+ cells can proliferate spontaneously in vitro and express HTLV-I antigens it has been shown that there is a predominant expansion of CD8+ T-cells, including HTLV-I-Tax-specific CD8+ T-cells, during spontaneous proliferation.

In this issue of Virulence, Norris and colleagues (ref. ¹¹) now show that in addition to T cells, natural killer cells (NK) cells also undergo significant spontaneous proliferation in HTLV-I infected subjects. NK cells are thought to contribute to susceptibility and/or protection from disease as a critical regulator of innate and adaptive immunity.¹² These cells are functionally cytotoxic that interact with macrophages, T and B cells, dendritic cells and endothelial cells to control immune responses.¹³ NK cells can both respond to and secrete a wide variety of cytokines during an inflammatory response and have been associated with an immunoregulatory role in autoimmune disease.¹³ Similar to what has been observed for in vitro spontaneous lymphoproliferation of T cells from HAM/TSP patients, Norris et al.¹¹ demonstrates that spontaneous NK cell proliferation also correlates with HTLV-I proviral load. They go on to suggest the possibility that in addition to NK cells, other non- T cell subsets including dendritic cells or monocytes might also undergo spontaneous proliferation.

What are the potential consequences of spontaneous lymphoproliferation particularly in HTV-I associated neurologic disease? A number of mechanisms have been proposed to explain the pathogenesis of HAMTSP based on HTLV-I pathology, disease association, and cellular immune reactivity. Three major models have be considered;¹⁴ (1) recognition of HTLV-I gene products in the CNS by antigen specific CD8+ effector CTL that result in lysis of glial elements or cytokine release (2) an autoaggressive bystander model mediated by immunocompetent virus-specific T cells releasing a cascade of cytokines which result in CNS damage; and (3) an autoimmune process in which HTLV-I infection leads to activation of autoreactive T cells. All these models of HTLV-I pathogenesis share a common feature immune mediated response in the affected organ to either specific viral antigen(s) or crossreactive self peptides. These immune mediated responses invariably must entail the localized proliferation of either the effector or regulatory cell either in the periphery and/or in the affected organ. While in HAM/TSP there is no direct in vivo correlate for spontaneous lymphoproliferating PBMC, the observations in this study by Norris¹¹ as well as others, suggests that in vitro spontaneous lymphoproliferation may be used as a surrogate marker for virus-host immunological interactions that may occur in vivo. Indeed, this new work broadens our thinking as to which cell types may be playing important roles in the neuropathogenesis of HAM/TSP. The elucidation of the role of these and other proliferating cells in HAM/TSP may reflect similar mechanisms in other diseases with viral etiologies.